Benzo-fused compounds for use in treating metabolic disorders

ABSTRACT

The present invention provides compounds useful, for example, for treating metabolic disorders in a subject. Such compounds have the general formula I: 
     
       
         
         
             
             
         
       
     
     where the definitions of the variables 
     
       
         
         
             
             
         
       
     
     and A are provided herein. The present invention also provides compositions that include, and methods for using, the compounds in preparing medicaments and for treating metabolic disorders such as, for example, type II diabetes.

1. CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/843,262, filed on Sep. 7, 2006, which is hereby incorporated byreference in its entirety and for all purposes as if fully set forthherein.

2. FIELD OF THE INVENTION

The present invention relates to compounds capable of modulating theG-protein-coupled receptor GPR40, compositions comprising the compounds,and methods for their use for controlling insulin levels in vivo and forthe treatment of conditions such as type II diabetes, hypertension,ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia andrelated disorders associated with abnormally high or low plasmalipoprotein, triglyceride or glucose levels.

3. BACKGROUND OF THE INVENTION

The production of insulin is central to the regulation of carbohydrateand lipid metabolism. Insulin imbalances lead to conditions such as typeII diabetes mellitus, a serious metabolic disease that afflicts around5% of the population in Western Societies and over 150 million peopleworldwide. Insulin is secreted from pancreatic β cells in response toelevated plasma glucose which is augmented by the presence of fattyacids. The recent recognition of the function of the G-protein coupledreceptor GPR40 in modulating insulin secretion has provided insight intoregulation of carbohydrate and lipid metabolism in vertebrates, andfurther provided targets for the development of therapeutic agents fordisorders such as obesity, diabetes, cardiovascular disease anddyslipidemia.

GPR40 is a member of the gene superfamily of G-protein coupled receptors(“GPCRs”). GPCRs are membrane proteins characterized as having sevenputative transmembrane domains that respond to a variety of molecules byactivating intra-cellular signaling pathways critical to a diversity ofphysiological functions. GPR40 was first identified as an orphanreceptor (i.e., a receptor without a known ligand) from a human genomicDNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun.239: 543-547. GPR40 is highly expressed in pancreatic β cells andinsulin-secreting cell lines. GPR40 activation is linked to modulationof the G_(q) family of intra-cellular signaling proteins and concomitantinduction of elevated calcium levels. It has been recognized that fattyacids serve as ligands for GPR40, and that fatty acids regulate insulinsecretion through GPR40. Itoh et al. (2003) Nature 422:173-176; Briscoeet al. (2003) J. Biol. Chem. 278:11303-11311; Kotarsky et al. (2003)Biochem. Biophys. Res. Commun. 301: 406-410.

Various documents have disclosed compounds reportedly having activitywith respect to GPR40. For example, WO 2004/041266 and EP 1559422disclose compounds that purportedly act as GPR40 receptor functionregulators. WO 2004/106276 and EP 1630152 are directed to condensed ringcompounds that purportedly possess GPR40 receptor function modulatingaction. More recently, WO 2005/086661, U.S. Patent Publication No.2006/0004012, US Patent Publication No. 2006/0270724, and US PatentPublication No. 2007/0066647 disclose compounds useful for modulatinginsulin levels in subjects and useful for treating type II diabetes.

Although a number of compounds have been disclosed that reportedlymodulate GPR40 activity, the prevalence of type II diabetes, obesity,hypertension, cardiovascular disease and dyslipidemia underscores theneed for new therapies to effectively treat or prevent these conditions.

4. SUMMARY OF THE INVENTION

Provided herein are compounds, pharmaceutical compositions and methodsuseful for treating or preventing a condition or disorder such as typeII diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema.

In one aspect, the present invention provides a compound having theformula I or a pharmaceutically acceptable salt, solvate, stereoisomer,or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof:

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond. In some such embodiments, Q is H.

represents an optionally substituted benzo-fused (C₅-C₈)cycloalkane ringcomprising a benzene ring fused to a (C₅-C₈) cycloalkane ring, anoptionally substituted heterobenzo-fused (C₅-C₈)cycloalkane ringcomprising a six-membered heteroaryl ring comprising 1 or 2 N atomsfused to a (C₅-C₈) cycloalkane ring, or a heteroaryl-fused(C₅-C₈)cycloalkane ring comprises a five-membered heteroaryl ringcomprising 1 or 2 heteroatoms fused to a (C₅-C₈)cycloalkane ring,wherein the benzene ring of the benzo-fused (C₅-C₈)cycloalkane ring, theheteroaryl ring of the heterobenzo-fused (C₅-C₈)cycloalkane ring, or theheteroaryl ring of the heteroaryl-fused (C₅-C₈)cycloalkane ring isbonded to L² or M, if L² is a bond. In some embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is a heterobenzo-fused (C₅-C₈)cycloalkane ring. In some suchembodiments, the heteroaryl ring of the heterobenzo-fused(C₅-C₈)cycloalkane ring comprises 1 N atom. In other such embodiments,the heteroaryl ring of the heterobenzo-fused (C₅-C₈)cycloalkane ringcomprises 2 N atoms. In some embodiments,

is a substituted heterobenzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted heterobenzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is a heteroaryl-fused (C₅-C₈)cycloalkane ring. In some such embodiments,the heteroaryl ring of the heteroaryl-fused (C₅-C₈)cycloalkane ringcomprises 1 N atom. In some embodiment the heteroaryl ring of theheteroaryl-fused (C₅-C₈)cycloalkane ring comprises 1 N atom and either 1O atom or 1 S atom. In other such embodiments, the heteroaryl ring ofthe heteroaryl-fused (C₅-C₈)cycloalkane ring comprises 2 N atoms. Insome embodiments,

is a substituted heteroaryl-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted heteroaryl-fused (C₅-C₈)cycloalkane ring. In someembodiments, the (C₅-C₈)cycloalkane ring of the benzo-fused(C₅-C₈)cycloalkane ring, the heterobenzo-fused (C₅-C₈)cycloalkane ring,or the heteroaryl-fused (C₅-C₈)cycloalkane ring of

comprises 0-3 heteroatoms selected from O, N, or S. In some suchembodiments, the cycloalkane ring comprises 1 or 2 heteroatom ringmembers selected from O or N, and in some embodiments 1 heteroatom ringmember, selected from O or N. In some such embodiments, the cycloalkanecomprises 0 heteroatom ring atoms such that each of the cycloalkane ringmembers of the benzo-fused (C₅-C₈)cycloalkane, the heterobenzo-fused(C₅-C₈)cycloalkane, or the heteroaryl-fused (C₅-C₈)cycloalkane ring is acarbon atom. In some such embodiments,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring). In some embodiments,

is a heteroaryl-fused (C₅-C₈)cycloalkane ring and the heteroaryl of theheteroaryl-fused (C₅-C₈)cycloalkane ring is selected from pyrrole,furan, thiophene, imidazole, thiazole, or oxazole.

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₂-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂. In someembodiments, L² is selected from (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene,oxymethylene, O, or S(O)_(k). In some embodiments, L² is selected from—CH₂—, substituted oxymethylene, or O. In some embodiments, L² isselected from —CH₂—O— or —CH(CH₃)—O—. In some embodiments, L² isselected from —CH₂—O— or an alkyl-substituted oxymethylene. In certainembodiments, L² is O or S(O)_(k).

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl. In some embodiments, M is an aromatic ring or is aheteroaromatic ring. In certain embodiments, M is a monocyclic aromaticor is a monocyclic heteroaromatic ring. In some embodiments, M is anunsubstituted monocyclic aromatic ring or is an unsubstituted monocyclicheteroaromatic ring. In certain embodiments, M is a substituted benzenering. In other embodiments, M is an unsubstituted benzene ring. In someembodiments, M is a heteroaromatic ring comprising six ring members. Insome such embodiments, the heteroaromatic ring comprises 1 or 2 N atoms.In some such embodiments, the heteroaromatic ring comprises 1 N atom,and in other such embodiments, the heteroaromatic ring comprises 2 Natoms.

X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k), where the subscript k is 0,1, or 2. In some embodiments X is a CR¹R^(1′).

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene. In some embodiments,L³ is a (C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene. In certainembodiments, L³ is (C₁-C₃)alkylene. In some embodiments, L³ ismethylene. In certain embodiments, L³ is a methylene substituted with amonocyclic aryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In some embodiments, Ais —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃,thiazolidinedionyl, hydroxyphenyl, or pyridyl. In certain embodiments, Ais —CO₂H or a salt thereof. In some embodiments, A is —CO₂H or an alkylester thereof. In some such embodiments, A is a C₁-C₆ alkyl ester suchas a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl. In certain embodiments, R^(a) is (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

R¹ is cyano, aryl, heteroaryl, a heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³. In any ofthe embodiments described herein, the heterocycle of theheterocycloalkyl R¹ group may be a saturated or unsaturated heterocyclecomprising from 5-7 ring members of which from 1-4 are heteroatomsselected from O, S, or N with the balance of the ring members being C.In some embodiments, R¹ is a group other than a group of the followingformula:

In certain embodiments, R¹ is selected from (C₂-C₈)alkynyl, aryl,heteroaryl, heterocycloalkyl, or —C(O)NR²R³. In some embodiments, R¹ isselected from aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)alkynyl. In other embodiments,R¹ is selected from R¹ is selected from heteroaryl or heterocycloalkyl.In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In some such embodiments, R¹ is selected from asubstituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In certain embodiments, R¹ is selected fromthe group consisting of prop-1-ynyl, phenyl, or a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl,furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some suchembodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In certain embodiments, R¹ isselected from the group consisting of prop-1-ynyl, phenyl, or asubstituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl. In some embodiments, R^(1′) ishydrogen or methyl. In some such embodiments, R^(1′) is hydrogen.

R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl. Optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S. The ring formed by combining R² and R³ may be a saturated,unsaturated, or aromatic ring.

The subscript k is, in each instance, independently selected from 0, 1,or 2. In some embodiments, k is 0.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug of the tautomer; or amixture thereof.

In certain embodiments, the present invention provides a compound havingthe formula II or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where Q is selected from hydrogen, aryl, or heteroaryl; L² is selectedfrom (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O, orS(O)_(k); R¹ is selected from (C₂-C₈)alkynyl, aryl, heteroaryl,heterocycloalkyl, or —C(O)NR²R³; R² and R³ are independently selectedfrom hydrogen or (C₁-C₄)alkyl; R⁴ is independently selected fromsubstituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″ R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″ SO₂R, —CN, —(C₂-C₅)alkynyl, —(C₂-C₅)alkenyl, or —NO₂, where R′, R″and R′″ each independently refer to hydrogen, unsubstituted (C₁-C₈)alkylor heteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ is independentlyselected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; thesubscript k is 0, 1 or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3, or 4. Insome such embodiments, R⁴ is independently selected from (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro. In certain embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring selected from substituted orunsubstituted dihydroindene, tetrahydronaphthalene,tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene. In certainembodiments, R¹ is selected from 1-propynyl, substituted orunsubstituted phenyl, heteroaryl, or heterocycloalkyl. In some suchembodiments, R¹ is selected from substituted or unsubstitutedheteroaryl, or heterocycloalkyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl;imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. Incertain embodiments, the subscript p is 0. In some such embodiments, R¹is selected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl,furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some suchembodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl.

It will be apparent that, in certain embodiments of formula II, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaIIIA or IIIB or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a tautomer, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula II comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula II comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula II comprises a mixture of S- andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula II; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula II, IIIA, and IIIB, the hydrogen on thecarboxylic group in formula II is replaced with an alkyl group to forman ester. For example, the compound of the present invention can be amethyl or ethyl ester of the compound of formula II.

In certain embodiments of the compound of formula I, the compound hasthe formula IV or is a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; one of R⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the othersof R⁶ and R^(6′) are independently selected from H, (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro, or one of R⁶ and one of R^(6′)on adjacent or non-adjacent carbon atoms, or on the same carbon atom,may join together to form a C₅-C₈ cycloalkane ring, or two of R⁶ or twoof R^(6′), on adjacent or non-adjacent carbon atoms, may join togetherto form a C₅-C₈ cycloalkane ring; the subscript n′ is 0, 1, 2, or 3; andthe subscript m is 1, 2, 3, or 4.

In some embodiments, the compound of formula IV comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula IV comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula IV comprises a mixture of S- andR-enantiomers.

In some embodiments, the compound of formula IV has the formula V:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

In some embodiments, the compound of formula IV or V, the compound hasthe formula VI:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

It will be apparent that, in certain embodiments of formula VI, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaVIA or VIB or a pharmaceutically acceptable salt, solvate, or prodrugthereof or a tautomer, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula VI comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula VI comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula VI comprises a mixture of S- andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula II; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula IV, V, VI, VIA, and VIB, A is —CO₂H or isa salt thereof. In some embodiments, the hydrogen on the carboxylicgroup of A is replaced with an alkyl group to form an ester. Forexample, the compound of the present invention can be a methyl or ethylester of the compound of formula IV, V, VI, VIA, or VIB.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,the subscript m is 1 or 2.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,the subscript m is 1 or 2; the subscript n′ is 0; L¹ is a bond; L² isselected from —CH₂—O—, substituted oxymethylene, or O; R¹ is selectedfrom aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)alkynyl; R^(1′) is H; and A is —CO₂H.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,Q is H; L³ is CH₂; and L² is —CH₂—O— or —CH(CH₃)—O—.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,R⁶ and R^(6′) are independently selected from H and (C₁-C₆)alkyl and atleast two of R⁶ and R^(6′) are (C₁-C₆)alkyl. In some such embodiments,R⁶ and R^(6′) are independently selected from H and methyl and at leasttwo of R⁶ and R^(6′) are methyl groups. In some such embodiments, two ofR⁶ and R^(6′) are methyl groups. In some embodiments, R⁶ and R^(6′) areindependently selected from H and methyl and at least four of R⁶ andR^(6′) are methyl groups. In some such embodiments, R⁶ and R^(6′) areindependently selected from H and methyl and four of R⁶ and R^(6′) aremethyl groups.

In some embodiments of the compounds of formula I, II, III, IIIA, IIIB,IV, V, VI, VIA, and VIB, R¹ is selected from heteroaryl orheterocycloalkyl. In some such embodiments, R¹ is selected from asubstituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl,thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In certainsuch embodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl;or dihydroisoxazol-3-yl. In still further such embodiments, R¹ isselected from a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In certain such embodiments, R¹is selected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; oxazol-2-yl.

In certain embodiments, the compound has the formula VIIA, VIIB, VIIC,or VIID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula VIIA, VIIB, VIIC, orVIID, has the formula VIIIA, VIIIB, VIIIC, or VIIID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula VIIIA, VIIIB, VIIC, orVIIID, has the formula IXA, IXB, IXC, or IXD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula VIIA, VIIB, VIIC,VIID, VIIIA, VIIIB, VIIIC, VIIID, IXA, IXB, IXC, or IXD, L² is —CH₂—O—or an alkyl-substituted oxymethylene; the subscript n′ is 0; R¹ is(C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl; R^(1′) is H; and A is—CO₂H. In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In still further such embodiments, R¹ is selectedfrom a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In some embodiments, thecompound is a compound of formula VIIA. In some embodiments, thecompound is a compound of formula VIIB. In some embodiments, thecompound is a compound of formula VIIC. In some embodiments, thecompound is a compound of formula VIID. In some embodiments, thecompound is a compound of formula VIIIA. In some embodiments, thecompound is a compound of formula VIIIB. In some embodiments, thecompound is a compound of formula VIIIC. In some embodiments, thecompound is a compound of formula VIIID. In some embodiments, thecompound is a compound of formula IXA. In some embodiments, the compoundis a compound of formula IXB. In some embodiments, the compound is acompound of formula IXC. In some embodiments, the compound is a compoundof formula IXD.

In certain embodiments, the compound of formula IXA, IXB, IXC, or IXD,has the formula XA, XB, XC, or XD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula XA, XB, XC, or XD, L²is —CH₂—O— or an alkyl-substituted oxymethylene; the subscript n′ is 0;R¹ is (C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl; and R^(1′) is H.In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In still further such embodiments, R¹ is selectedfrom a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In some embodiments, thecompound is a compound of formula XA. In some embodiments, the compoundis a compound of formula XB. In some embodiments, the compound is acompound of formula XC. In some embodiments, the compound is a compoundof formula XD.

The compounds of the invention include pharmaceutically acceptablesalts, solvates, stereoisomers, and prodrugs thereof, and tautomers andpharmaceutically acceptable salts, solvates, stereoisomers, and prodrugsthereof, and mixtures thereof. In some embodiments, the compounds arepharmaceutically acceptable salts. In other embodiments, the compoundsare prodrugs such as esters of a carboxylic acid.

In certain embodiments of the compound of formula I, the compound hasthe formula of any one of XIa-XIm or is a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a mixture thereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; the subscript n′ is 0, 1, 2, or 3; and R^(d) is selected fromoptionally substituted C₁-C₆ alkyl or optionally substituted aryl.

In some embodiments, the compound of any one of formula XIa-XImcomprises a stereomerically pure S-enantiomer. In other embodiments, thecompound comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound comprises a mixture of S- and R-enantiomers.

In certain embodiments of the compound of formula I, the compound hasthe formula of any one of XIIa-XIIm or is a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a mixture thereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″ SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; R⁶ and R^(6′) are independently selected from H, (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro; Z is selected from O, NR^(d),or S; R^(d) is selected from optionally substituted C₁-C₆ alkyl oroptionally substituted aryl; the subscript n′ is 0, 1, 2, or 3; and thesubscript n″ is 0, 1, or 2.

In some embodiments, the compound of any one of formula XIIa-XIImcomprises a stereomerically pure S-enantiomer. In other embodiments, thecompound comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound comprises a mixture of S- and R-enantiomers.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier, diluent, or excipient,and a compound of any of the embodiments of the invention.

In another aspect, the invention provides methods for treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, hypertension,cancer, and edema. Such methods include administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe embodiments. In some such embodiments, the disease or condition istype II diabetes. In some embodiments, a compound of any of theembodiments is administered with combination with a second therapeuticagent. In some such embodiments, the second therapeutic agent ismetformin or is a thiazolidinedione. The second therapeutic agent may beadministered before, during, or after administration of the compound ofany of the embodiments.

In another aspect, the invention provides methods for treating orpreventing a disease or condition responsive to the modulation of GPR40.Such methods include administering to a subject in need thereof, atherapeutically effective amount of a compound of any of theembodiments.

In another aspect, the invention provides methods for treating orpreventing a disease or condition mediated, regulated, or influenced bypancreatic β cells. Such methods include administering to a subject inneed thereof, a therapeutically effective amount of a compound of any ofthe embodiments.

In another aspect, the invention provides methods for modulating GPR40function in a cell. Such methods include contacting a cell with acompound of formula any of the embodiments.

In another aspect, the invention provides methods for modulating GPR40function. Such methods include contacting GPR40 with a compound of anyof the embodiments.

In another aspect, the invention provides methods for modulatingcirculating insulin concentration in a subject. Such methods includeadministering a compound of any of the embodiments to the subject. Insome such embodiments, the circulating insulin concentration isincreased in the subject after administration whereas in other suchembodiments, the circulating insulin concentration is decreased in thesubject after administration.

In another aspect, the invention provides the use of a compound of anyof the embodiments for treating a disease or condition or for preparinga medicament for treating a disease or condition where the disease orcondition is selected from the group consisting of type II diabetes,obesity, hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.In some such embodiments, the disease or condition is type II diabetes.The compounds of the invention may also be used to prepare medicamentsthat include a second therapeutic agent such as metformin or athiazolidinedione.

In another aspect, the invention provides the use of a compound of anyof the embodiments for modulating GPR40 or for use in the preparation ofa medicament for modulating GPR40.

In another aspect, the invention provides a therapeutic composition thatincludes a compound of any of the embodiments and a second therapeuticagent such as those described herein, for example, metformin or athiazolidinedione, as a combined preparation for simultaneous, separate,or sequential use in the treatment of a disease or condition mediated byGPR40. In some such embodiments, the disease or condition is type IIdiabetes. In some embodiments, the compound of any of the embodimentsand the second therapeutic agent are provided as a single composition,whereas in other embodiments they are provided separately as parts of akit.

In one aspect, the invention provides a method of synthesizing acompound of formula XV as shown in Scheme 2. The method includes:reacting a compound of formula XIII with a compound of formula XIV toproduce the compound of formula XV, wherein the compounds of formulaXIII, XIV, and XV have the following structures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)alkynyl, or —C(O)NR²R³; R² and R³ are independently selected fromhydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl; optionally, R² and R³ arecombined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogenatom to which they are attached comprising from 0 to 2 additionalheteroatoms selected from N, O, or S; and; R⁵ is independently selectedfrom (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; p isselected from 0, 1, 2, 3, or 4; z is selected from 1, 2, or 3; R^(4′) isindependently selected from substituted (C₁-C₆)alkyl, —R′, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, wherein R′, R″ and R′″ are each independentlyselected from hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; n′ is 0, 1, 2, or 3; m is 1, 2, 3, or 4; oneof R⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the others of R⁶ andR^(6′) are independently selected from H, (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or nitro, wherein one of R⁶ and one of R^(6′) onadjacent or non-adjacent carbon atoms, or on the same carbon atom mayjoin together to form a C₅-C₈ cycloalkane ring, or two of R⁶ or two ofR^(6′), on adjacent or non-adjacent carbon atoms, may join together toform a C₅-C₈ cycloalkane ring; L¹ is selected from a bond,(C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)); R^(a) is selected fromhydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or (C₂-C₆)heteroalkyl; R^(b)is selected from hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; Q isselected from hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; W is a leaving group; and further wherein, thecompounds of formula XIII and XV can be a mixture of compounds havingthe R and S stereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.

In some embodiments, W is selected from OH or a halogen. In some suchembodiments, W is OH and a phosphine selected from a trialkylphosphine,a dialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphineand an azodicarboxylate are used to react the compound of formula XIIIwith the compound of formula XIV. In other such embodiments, W is ahalogen selected from Br or Cl, and a base is used to react the compoundof formula XXII with the compound of formula XXIII. In some embodiments,W is selected from OH, a halogen, OTs, OMs, or OTf, where OTs istosylate, OMs is mesylate, and OTf is triflate and Ts isp-toluenesulfonyl, Ms is methanesulfonyl, and Tf istrifluoromethanesulfonyl.

In some embodiments, Alk is selected from methyl or ethyl.

In some embodiments, m is 1 or 2.

In some embodiments, n′ is 0

In some embodiments, z is 1.

In some embodiments, the method further includes removing the Alk groupof the compound of formula XV to form a compound of formula XVI or asalt thereof, and the compound of formula XVI has the followingstructure:

wherein the variables have the definitions provided with respect to thecompounds of any of the embodiments of formula XIII, XIV, and XV. Insome such embodiments, the compound of formula XV is reacted in thepresence of a hydroxide base to produce the compound of formula XVI. Insome such embodiments, the hydroxide base is selected from LiOH, NaOH,KOH, or Ca(OH)₂.

Other objects, features and advantages of the invention will becomeapparent to those skilled in the art from the following description andclaims.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Abbreviations andDefinitions

The terms “treat”, “treating” and “treatment”, as used herein, are meantto include alleviating or abrogating a condition or disease and/or itsattendant symptoms. The terms “prevent”, “preventing” and “prevention”,as used herein, refer to a method of delaying or precluding the onset ofa condition or disease and/or its attendant symptoms, barring a subjectfrom acquiring a condition or disease, or reducing a subject's risk ofacquiring a condition or disease.

The term “therapeutically effective amount” refers to that amount of thecompound that will elicit the biological or medical response of atissue, system, or subject that is being sought. The term“therapeutically effective amount” includes that amount of a compoundthat, when administered, is sufficient to prevent development of, oralleviate to some extent, one or more of the symptoms of the conditionor disorder being treated in a subject. The therapeutically effectiveamount in a subject will vary depending on the compound, the disease andits severity, and the age, weight, etc., of the subject to be treated.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function or activity of GPR40either directly or indirectly. Inhibitors are compounds that, forexample, bind to, partially or totally block stimulation, decrease,prevent, delay activation, inactivate, desensitize, or down regulatesignal transduction, such as, for instance, antagonists. Activators arecompounds that, for example, bind to, stimulate, increase, activate,facilitate, enhance activation, sensitize or up regulate signaltransduction, such as agonists for instance. Modulation may occur invitro or in vivo.

As used herein, the phrases “GPR40-mediated condition or disorder”,“disease or condition mediated by GPR40”, and the like refer to acondition or disorder characterized by inappropriate, for example, lessthan or greater than normal, GPR40 activity. A GPR40-mediated conditionor disorder may be completely or partially mediated by inappropriateGPR40 activity. However, a GPR40-mediated condition or disorder is onein which modulation of GPR40 results in some effect on the underlyingcondition or disease (e.g., a GPR40 modulator results in someimprovement in patient well-being in at least some patients). ExemplaryGPR40-mediated conditions and disorders include cancer and metabolicdisorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis,hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X andrelated disorders, e.g., cardiovascular disease, atherosclerosis, kidneydisease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, and edema.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which is fully saturated,having the number of carbon atoms designated (e.g., C₁-C₁₀ means one toten carbons). Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs andisomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike.

The term “alkenyl”, by itself or as part of another substituent, means astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be mono- or polyunsaturated, having thenumber of carbon atoms designated (i.e., C₂-C₈ means two to eightcarbons) and one or more double bonds. Examples of alkenyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), and higher homologs and isomersthereof.

The term “alkynyl”, by itself or as part of another substituent, means astraight or branched chain hydrocarbon radical, or combination thereof,which may be mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e., C₂-C₈ means two to eight carbons) and one or moretriple bonds. Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and higher homologs and isomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from alkyl, as exemplified by —CH₂CH₂CH₂CH₂—.Typically, an alkyl (or alkylene) group will have from 1 to 24 carbonatoms, with those groups having 12 or fewer carbon atoms being preferredin the present invention. A “lower alkyl” or “lower alkylene” is ashorter chain alkyl or alkylene group, generally having eight or fewercarbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Similarly, the term dialkylaminorefers to an amino group having two attached alkyl groups. The alkylgroups of a dialkylamino may be the same or different.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of O, N, and S, and wherein the nitrogen and sulfur atoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N, and S may be placed at any positionof the heteroalkyl group. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, and —CH₂—CH═N—OCH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃. When a prefix such as(C₂-C₈) is used to refer to a heteroalkyl group, the number of carbons(2 to 8, in this example) is meant to include the heteroatoms as well.For example, a C₂-heteroalkyl group is meant to include, for example,—CH₂OH (one carbon atom and one heteroatom replacing a carbon atom) and—CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group is an, oxyalkyl group. Forinstance, (C₂-C₅)oxyalkyl is meant to include, for example —CH₂—O—CH₃ (aC₃-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, and the like.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied. Heteroalkylenegroups such as oxymethyl groups (—CH₂—O—) may be substituted orunsubstituted. In some embodiments, heteroalkylene groups may besubstituted with an alkyl group. For example, the carbon atom of anoxymethylene group may be substituted with a methyl group in a group offormula —CH(CH₃)—O—.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Thus, the terms“cycloalkyl” and “heterocycloalkyl” are meant to be included in theterms “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, 4,5-dihydroisoxazol-3-yl, and the like.The term “heterocycloalkyl” includes fully saturated compounds such aspiperidine and compounds with partial saturation that are not aromatic.Examples of such groups include, but are not limited to, an imidazole,oxazole, or isoxazole which has been partially hydrogenated so that itonly contains one double bond.

The term “cycloalkylene” and “heterocycloalkylene,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkylene” and “heteroalkylene,” respectively. Thus, theterms “cycloalkylene” and “heterocycloalkylene” are meant to be includedin the terms “alkylene” and “heteroalkylene,” respectively.Additionally, for heterocycloalkylene, one or more heteroatoms canoccupy positions at which the heterocycle is attached to the remainderof the molecule. Typically, a cycloalkylene or heterocycloalkylene willhave from 3 to 9 atoms forming the ring, more typically, 4 to 7 atomsforming the ring, and even more typically, 5 or 6 atoms will form thecycloalkylene or heterocycloalkylene ring.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl”, aremeant to include alkyl substituted with halogen atoms which can be thesame or different, in a number ranging from one to (2m′+1), where m′ isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C₁-C₄)alkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus,the term “haloalkyl” includes monohaloalkyl (alkyl substituted with onehalogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms ina number ranging from two to (2m′+1) halogen atoms). The term“perhaloalkyl” means, unless otherwise stated, alkyl substituted with(2m′+1) halogen atoms, where m′ is the total number of carbon atoms inthe alkyl group. For example, the term “perhalo(C₁-C₄)alkyl”, is meantto include trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon substituent which can be a single ringor multiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from the group consistingof N, O and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of aryl and heteroarylgroups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl,5-benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1H-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 7-quinolyl, and 8-quinolyl.

Preferably, the term “aryl” refers to a phenyl or naphthyl group whichis unsubstituted or substituted. Preferably, the term “heteroaryl”refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl,oxadiazolyl, isoxazolyl, thiazolyl, furyl, thienyl (thiophenyl),pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl,isoquinolyl, triazolyl, tetrazolyl, quinoxalinyl, or quinolyl groupwhich is unsubstituted or substituted.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylalkoxy, arylthioxy, arylalkyl) includes both aryland heteroaryl rings as defined above. Thus, the term “arylalkyl” ismeant to include those radicals in which an aryl group is attached to analkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like)including those alkyl groups in which a carbon atom (e.g., a methylenegroup) has been replaced by, for example, an oxygen atom (e.g.,phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and thelike). As another example, the term “aryl(C₁-C₄)alkoxy” is mean toinclude radicals in which an aryl group is attached to an alkyl grouphaving 1 to 4 carbon atoms that is bonded to an O which is attached tothe rest of the molecule. Examples include substituted and unsubstitutedphenylmethoxy, phenylethoxy, phenylpropoxy, pyridylmethoxy, and thelike.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical, unless otherwise indicated. Preferredsubstituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as thosegroups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, —N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, and —NO₂, in a number ranging from zero to three, withthose groups having zero, one or two substituents being particularlypreferred. Other suitable substituents include aryl and heteroarylgroups. R′, R″ and R′″ each independently refer to hydrogen,unsubstituted (C₁-C₈)alkyl and heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups. WhenR′ and R″ are attached to the same nitrogen atom, they can be combinedwith the nitrogen atom to form a 5-, 6- or 7-membered ring. For example,—NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Typically, an alkyl or heteroalkyl group will have from zero to threesubstituents, with those groups having two or fewer substituents beingpreferred in the present invention. More preferably, an alkyl orheteroalkyl radical will be unsubstituted or monosubstituted. Mostpreferably, an alkyl or heteroalkyl radical will be unsubstituted. Fromthe above discussion of substituents, one of skill in the art willunderstand that the term “alkyl” is meant to include groups such astrihaloalkyl (e.g., —CF₃ and —CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl and —NO₂, where R′ and R″ are as defined above. Furtherpreferred substituents are selected from: —OR′, ═O, —NR′R″, halogen,—OC(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′,—NR′—SO₂NR″R′″, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand are selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl,(unsubstituted aryl)oxy-(C₁-C₄)alkyl, —(C₂-C₅)alkynyl, and—(C₂-C₅)alkenyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—,—CH₂—, or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl. Otherwise, R′ is as defined above.

As used herein, the term “benzo-fused cycloalkane ring” is meant toinclude bicyclic structures in which benzene is fused with a cycloalkane(or cycloheteroalkane). To illustrate, in some embodiments, “benzo-fusedcycloalkane ring” includes the following structures:

As used herein, the term “heterobenzo-fused (C₅-C₈)cycloalkane ring” hasthe same meaning as “benzo-fused (C₅-C₈)cycloalkane ring” except thebenzene of the benzo-fused (C₅-C₈)cycloalkane ring is replaced with asix-membered heteroaryl ring comprising 1 or 2 nitrogen (N) atoms. Asindicated in the structures shown above, the (C₅-C₈)cycloalkane ofbenzo-fused (C₅-C₈)cycloalkane rings and heterobenzo-fused(C₅-C₈)cycloalkane ring may include only carbon atoms, but may alsoinclude one or more heteroatoms. Such heteroatoms typically are selectedfrom O, N, or S.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

The term “pharmaceutically acceptable salt” is meant to include a saltof the active compound which is prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on the compounddescribed herein. When a compound of the invention contains relativelyacidic functionalities, a base addition salt can be obtained bycontacting the neutral form of such compound with a sufficient amount ofthe desired base, either neat or in a suitable inert solvent. Examplesof pharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When a compound of the invention contains relatively basicfunctionalities, an acid addition salt can be obtained by contacting theneutral form of such compound with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginine and the like, and salts of organic acids likeglucuronic or galacturonic acids and the like (see, for example, Bergeet al. (1977) J. Pharm. Sci. 66:1-19). Certain specific compounds of theinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds of the invention. Additionally,prodrugs can be converted to the compounds of the invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the invention when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. A wide variety of prodrug derivatives are known inthe art, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound of the invention which is administered as an ester(the “prodrug”), but then is metabolically hydrolyzed to the carboxylicacid, the active entity. Additional examples include peptidylderivatives of a compound.

As used herein, “solvate” refers to a compound of the present inventionor a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of solvent bound by non-covalentintermolecular forces. Where the solvent is water, the solvate is ahydrate.

Certain compounds of the invention may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the invention and are intended to be within thescope of the invention.

As known by those skilled in the art, certain compounds of the inventionmay exist in one or more tautomeric forms. Because one chemicalstructure may only be used to represent one tautomeric form, it will beunderstood that convenience, referral to a compound of a givenstructural formula includes tautomers of the structure represented bythe structural formula.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, enantiomers,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the invention.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line indicates that both stereoisomers areencompassed.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers, mixtures ofdiastereomers or enantiomerically or optically pure compounds. Thisinvention encompasses the use of stereomerically pure forms of suchcompounds, as well as the use of mixtures of those forms. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular compound of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, 1N, 1972).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic or prophylactic agents, research reagents, e.g., GPR40 assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe invention.

5.2 Embodiments of the Invention

In one aspect, a class of compounds that modulates GPR40 is describedherein. Depending on the biological environment (e.g., cell type,pathological condition of the subject, etc.), these compounds canmodulate, e.g., activate or inhibit, the actions of GPR40. By modulatingGPR40, the compounds find use as therapeutic agents capable ofregulating insulin levels in a subject. The compounds find use astherapeutic agents for modulating diseases and conditions responsive tomodulation of GPR40 and/or mediated by GPR40 and/or mediated bypancreatic p cells. As noted above, examples of such diseases andconditions include diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, cancer, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis,hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, nephropathy, thrombotic disorders,diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia andedema. Additionally, the compounds are useful for the treatment and/orprevention of complications of these diseases and disorders (e.g., typeII diabetes, sexual dysfunction, dyspepsia and so forth).

While the compounds of the invention are believed to exert their effectsby interacting with GPR40, the mechanism of action by which thecompounds act is not a limiting embodiment of the invention.

Compounds contemplated by the invention include, but are not limited to,the exemplary compounds provided herein.

5.2.1 Compounds

In one aspect, the present invention provides a compound having theformula I or a pharmaceutically acceptable salt, solvate, stereoisomer,or prodrug thereof; or a tautomer or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof:

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond. In some such embodiments, Q is H.

represents an optionally substituted benzo-fused (C₅-C₈)cycloalkane ringcomprising a benzene ring fused to a (C₅-C₈)cycloalkane ring, anoptionally substituted heterobenzo-fused (C₅-C₈)cycloalkane ringcomprising a six-membered heteroaryl ring comprising 1 or 2 N atomsfused to a (C₅-C₈)cycloalkane ring, or a heteroaryl-fused(C₅-C₈)cycloalkane ring comprises a five-membered heteroaryl ringcomprising 1 or 2 N heteroatoms, generally selected from O, N, and S,fused to a (C₅-C₈)cycloalkane ring, wherein the benzene ring of thebenzo-fused (C₅-C₈)cycloalkane ring, the heteroaryl ring of theheterobenzo-fused (C₅-C₈)cycloalkane ring, or the heteroaryl ring of theheteroaryl-fused (C₅-C₈)cycloalkane ring is bonded to L² or M, if L² isa bond. In some embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is a heterobenzo-fused (C₅-C₈)cycloalkane ring. In some suchembodiments, the heteroaryl ring of the heterobenzo-fused(C₅-C₈)cycloalkane ring comprises 1 N atom. For example, the heteroarylring of the heterobenzo-fused (C₅-C₈)cycloalkane ring may be a pyridinering. In other such embodiments, the heteroaryl ring of theheterobenzo-fused (C₅-C₈)cycloalkane ring comprises 2 N atoms. Forexample, the heteroaryl ring of the heterobenzo-fused (C₅-C₈)cycloalkanering may be a pyrimidine, pyrazine, or pyridazine ring. In someembodiments,

is a substituted heterobenzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted heterobenzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is a heteroaryl-fused (C₅-C₈)cycloalkane ring. In some such embodiments,the heteroaryl ring of the heteroaryl-fused (C₅-C₈)cycloalkane ringcomprises 1 N atom. In some embodiment the heteroaryl ring of theheteroaryl-fused (C₅-C₈)cycloalkane ring comprises 1 N atom and either 1O atom or 1 S atom. In other such embodiments, the heteroaryl ring ofthe heteroaryl-fused (C₅-C₈)cycloalkane ring comprises 2 N atoms. Insome embodiments,

is a substituted heteroaryl-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted heteroaryl-fused (C₅-C₈)cycloalkane ring. In someembodiments, the (C₅-C₈)cycloalkane ring of the benzo-fused(C₅-C₈)cycloalkane ring, the heterobenzo-fused (C₅-C₈)cycloalkane ring,or the heteroaryl-fused (C₅-C₈)cycloalkane ring of

comprises 0-3 heteroatoms selected from O, N, or S. In some suchembodiments, the cycloalkane ring comprises 1 or 2 heteroatom ringmembers selected from O or N, and in some embodiments 1 heteroatom ringmember, selected from O or N. In some such embodiments, the cycloalkanecomprises 0 heteroatom ring atoms such that each of the cycloalkane ringmembers of the benzo-fused (C₅-C₈)cycloalkane, the heterobenzo-fused(C₅-C₈)cycloalkane, or the heteroaryl-fused (C₅-C₈)cycloalkane ring is acarbon atom. In some such embodiments,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring). In some embodiments,

is a heteroaryl-fused (C₅-C₈)cycloalkane ring and the heteroaryl of theheteroaryl-fused (C₅-C₈)cycloalkane ring is selected from pyrrole,furan, thiophene, imidazole, thiazole, or oxazole.

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂. In someembodiments, L² is selected from (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene,oxymethylene, O, or S(O)_(k). In some embodiments, L² is selected from—CH₂—O—, substituted oxymethylene, or O. In some embodiments, L² isselected from —CH₂—O— or —CH(CH₃)—O—. In some embodiments, L² isselected from —CH₂—O— or an alkyl-substituted oxymethylene. In certainembodiments, L² is O or S(O)_(k).

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl. In some embodiments, M is an aromatic ring or is aheteroaromatic ring. In certain embodiments, M is a monocyclic aromaticor is a monocyclic heteroaromatic ring. In some embodiments, M is anunsubstituted monocyclic aromatic ring or is an unsubstituted monocyclicheteroaromatic ring. In certain embodiments, M is a substituted benzenering. In other embodiments, M is an unsubstituted benzene ring. In someembodiments, M is a heteroaromatic ring comprising six ring members. Insome such embodiments, the heteroaromatic ring comprises 1 or 2 N atoms.In some such embodiments, the heteroaromatic ring comprises 1 N atom,and in other such embodiments, the heteroaromatic ring comprises 2 Natoms.

X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k), where the subscript k is 0,1, or 2. In some embodiments X is a CR¹R^(1′).

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene. In some embodiments,L³ is a (C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene. In certainembodiments, L³ is (C₁-C₃)alkylene. In some embodiments, L³ ismethylene. In certain embodiments, L³ is a methylene substituted with amonocyclic aryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In some embodiments, Ais —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃,thiazolidinedionyl, hydroxyphenyl, or pyridyl In certain embodiments, Ais —CO₂H or a salt thereof. In some embodiments, A is —CO₂H or an alkylester thereof. In some such embodiments, A is a C₁-C₆ alkyl ester suchas a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl. In certain embodiments, R^(a) is (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl. R¹ is cyano,aryl, heteroaryl, a heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³. In some embodiments, R¹is a group other than a group of the following formula:

In any of the embodiments described herein, the heterocycle of theheterocycloalkyl R¹ group may be a saturated or unsaturated heterocyclecomprising from 5-7 ring members of which from 1-4 are heteroatomsselected from O, S, or N with the balance of the ring members being C.In certain embodiments, R¹ is selected from (C₂-C₈)alkynyl, aryl,heteroaryl, heterocycloalkyl, or —C(O)NR²R³. In some embodiments, R¹ isselected from aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)alkynyl. In other embodiments,R¹ is selected from heteroaryl or heterocycloalkyl. In some suchembodiments, R¹ is selected from a substituted or unsubstitutedimidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In some such embodiments, R¹ is selected from asubstituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In certain embodiments, R¹ is selected fromthe group consisting of prop-1-ynyl, phenyl, or a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl,furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some suchembodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In certain embodiments, R¹ isselected from the group consisting of prop-1-ynyl, phenyl, or asubstituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some embodiments, R¹ is a(C₂-C₈)alkenyl or a (C₃-C₈)alkenyl group that may optionally besubstituted with groups such as aryl or heteroaryl. For example, in someembodiments, R¹ may be a an alkenyl group such as, but not limited to,the E and Z forms, where applicable, of one of the following: —CH═CH₂,—CH₂—CH═CH₂, —CH═CH—CH₃, —CH₂—CH₂—CH═CH₂, —CH₂—CH═CH—CH₃,—CH═CH—CH₂—CH₃, —C(CH₃)═CH₂, —CH(CH₃)—CH═CH₂, —CH₂—C(CH₃)═CH₂,—CH(CH₃)—CH₂—CH═CH₂, —CH₂—CH(CH₃)—CH═CH₂, —CH₂—CH₂—C(CH₃)═CH₂,—CH(CH₃)—CH═CH—CH₃, —CH₂—C(CH₃)═CH—CH₃, —CH₂—CH═C(CH₃)—CH₃,—C(CH₃)═CH—CH₂—CH₃, —CH═C(CH₃)—CH₂—CH₃, —CH═CH—CH(CH₃)—CH₃. Such R¹alkenyl groups may optionally be substituted with one or more aryl groupsuch as a benzene. For example, in some embodiments, the R¹ group may bea group such as a —CH═CH—CH₂CH₂-Phenyl group.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl. In some embodiments, R^(1′) ishydrogen or methyl. In some such embodiments, R^(1′) is hydrogen.

R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl. Optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S. The ring formed by combining R² and R³ may be a saturated,unsaturated, or aromatic ring.

The subscript k is, in each instance, independently selected from 0, 1,or 2. In some embodiments, k is 0.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug of the tautomer; or amixture thereof.

In certain embodiments, the present invention provides a compound havingthe formula II or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where Q is selected from hydrogen, aryl, or heteroaryl; L² is selectedfrom (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O, orS(O)_(k); R¹ is selected from (C₂-C₈)alkynyl, aryl, heteroaryl,heterocycloalkyl, or —C(O)NR²R³; R² and R³ are independently selectedfrom hydrogen or (C₁-C₄)alkyl; R⁴ is independently selected fromsubstituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′-SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″ SO₂R, —CN, —(C₂-C₅)alkynyl, —(C₂-C₅)alkenyl, or —NO₂, where R′, R″and R′″ each independently refer to hydrogen, unsubstituted (C₁-C₈)alkylor heteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ is independentlyselected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; thesubscript k is 0, 1, or 2; the subscript n is 0, 1, 2, 3, 4, 5,6, 7, 8,9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3, or 4. Insome such embodiments, R⁴ is independently selected from (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro. In certain embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring selected from substituted orunsubstituted dihydroindene, tetrahydronaphthalene,tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene. In certainembodiments, R¹ is selected from 1-propynyl, substituted orunsubstituted phenyl, heteroaryl, or heterocycloalkyl. In some suchembodiments, R¹ is selected from substituted or unsubstitutedheteroaryl, or heterocycloalkyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl;imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. Insome such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl;imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl; tetrazol-5-yl; oroxazol-2-yl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In certainembodiments, the subscript p is 0.

It will be apparent that, in certain embodiments of formula II, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaIIIA or IIIB or a pharmaceutically acceptable salt, solvate, or prodrugthereof or a tautomer, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula II comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula II comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula II comprises a mixture of S- andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula II; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula II, IIIA, and IIIB, the hydrogen on thecarboxylic group in formula II is replaced with an alkyl group to forman ester. For example, the compound of the present invention can be amethyl or ethyl ester of the compound of formula II.

In certain embodiments of the compound of formula I, the compound hasthe formula IV or is a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″ SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; one of R⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the othersof R⁶ and R^(6′) are independently selected from H, (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro, or one of R⁶ and one of R^(6′)on adjacent or non-adjacent carbon atoms, or on the same carbon atom,may join together to form a C₅-C₈ cycloalkane ring, or two of R⁶ or twoof R^(6′), on adjacent or non-adjacent carbon atoms, may join togetherto form a C₅-C₈ cycloalkane ring; the subscript n′ is 0, 1, 2, or 3; andthe subscript m is 1, 2, 3, or 4.

In some embodiments, the compound of formula IV comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula IV comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula IV comprises a mixture of S- andR-enantiomers.

In some embodiments, the compound of formula IV has the formula V:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

In some embodiments, the compound of formula IV or V, the compound hasthe formula VI:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

It will be apparent that, in certain embodiments of formula VI, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaVIA or VIB or a pharmaceutically acceptable salt, solvate, or prodrugthereof or a tautomer, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula VI comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula VI comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula VI comprises a mixture of S- andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula II; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula IV, V, VI, VIA, and VIB, A is —CO₂H or isa salt thereof. In some embodiments, the hydrogen on the carboxylicgroup of A is replaced with an alkyl group to form an ester. Forexample, the compound of the present invention can be a methyl or ethylester of the compound of formula IV, V, VI, VIA, or VIB.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,the subscript m is 1 or 2.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,the subscript m is 1 or 2; the subscript n′ is 0; L¹ is a bond; L² isselected from —CH₂—O—, substituted oxymethylene, or O; R¹ is selectedfrom aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)alkynyl; R^(1′) is H; and A is —CO₂H.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,Q is H; L³ is CH₂; and L² is —CH₂—O— or —CH(CH₃)—O—.

In some embodiments of the compounds of formula IV, V, VI, VIA, and VIB,R⁶ and R^(6′) are independently selected from H and (C₁-C₆)alkyl and atleast two of R⁶ and R^(6′) are (C₁-C₆)alkyl. In some such embodiments,R⁶ and R^(6′) are independently selected from H and methyl and at leasttwo of R⁶ and R^(6′) are methyl groups. In some such embodiments, two ofR⁶ and R^(6′) are methyl groups. In some embodiments, R⁶ and R^(6′) areindependently selected from H and methyl and at least four of R⁶ andR^(6′) are methyl groups. In some such embodiments, R⁶ and R^(6′) areindependently selected from H and methyl and four of R⁶ and R^(6′) aremethyl groups.

In some embodiments of the compounds of formula I, II, III, IIIA, IIIB,IV, V, VI, VIA, and VIB, R¹ is selected from heteroaryl orheterocycloalkyl. In some such embodiments, R¹ is selected from asubstituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl,thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In certainsuch embodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl;or dihydroisoxazol-3-yl. In still further such embodiments, R¹ isselected from a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In certain such embodiments, R¹is selected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl.

In certain embodiments, the compound has the formula VIIA, VIIB, VIIC,or VIID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula VIIA, VIIB, VIIC, orVIID, has the formula VIIIA, VIIIB, VIIIC, or VIIID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula VIIIA, VIIIB, VIIIC, orVIIID, has the formula IXA, IXB, IXC, or IXD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula VIIA, VIIB, VIIC,VIID, VIIIA, VIIIB, VIIIC, VIIID, IXA, IXB, IXC, or IXD, L² is —CH₂—O—or an alkyl-substituted oxymethylene; the subscript n′ is 0; R¹ is(C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl; R^(1′) is H; and A is—CO₂H. In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In still further such embodiments, R¹ is selectedfrom a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In some embodiments, thecompound is a compound of formula VIIA. In some embodiments, thecompound is a compound of formula VIIB. In some embodiments, thecompound is a compound of formula VIIC. In some embodiments, thecompound is a compound of formula VIID. In some embodiments, thecompound is a compound of formula VIIIA. In some embodiments, thecompound is a compound of formula VIIIB. In some embodiments, thecompound is a compound of formula VIIIC. In some embodiments, thecompound is a compound of formula VIIID. In some embodiments, thecompound is a compound of formula IXA. In some embodiments, the compoundis a compound of formula IXB. In some embodiments, the compound is acompound of formula IXC. In some embodiments, the compound is a compoundof formula IXD.

In certain embodiments, the compound of formula IXA, IXB, IXC, or IXD,has the formula XA, XB, XC, or XD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula XA, XB, XC, or XD, L²is —CH₂—O— or an alkyl-substituted oxymethylene; the subscript n′ is 0;R¹ is (C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl; and R^(1′) is H.In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In still further such embodiments, R¹ is selectedfrom a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some such embodiments, R¹ is selectedfrom a substituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;pyrimidin-5-yl; tetrazol-5-yl; or oxazol-2-yl. In still further suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; or oxazol-2-yl. In some embodiments, thecompound is a compound of formula XA. In some embodiments, the compoundis a compound of formula XB. In some embodiments, the compound is acompound of formula XC. In some embodiments, the compound is a compoundof formula XD.

In certain embodiments of the compound of formula I, the compound hasthe formula of any one of XIa-XIm or is a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a mixture thereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-C₄)alkyl groups;the subscript n′ is 0, 1, 2, or 3; and R^(d) is selected from optionallysubstituted C₁-C₆ alkyl or optionally substituted aryl.

In some embodiments, the compound of any one of formula XIa-XImcomprises a stereomerically pure S-enantiomer. In other embodiments, thecompound comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound comprises a mixture of S- and R-enantiomers.

In certain embodiments of the compound of formula I, the compound hasthe formula of any one of XIIa-XIIm or is a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof; or a tautomer, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a mixture thereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; R⁶ and R^(6′) are independently selected from H, (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro; Z is selected from O, NR^(d),or S; R^(d) is selected from optionally substituted C₁-C₆ alkyl oroptionally substituted aryl; the subscript n′ is 0, 1, 2, or 3; and thesubscript n″ is 0, 1, or 2.

In some embodiments, the compound of any one of formula XIIa-XIImcomprises a stereomerically pure S-enantiomer. In other embodiments, thecompound comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound comprises a mixture of S- and R-enantiomers.

5.2.2 Preparation of the Compounds

The compounds of the invention can be prepared by a variety of syntheticor semisynthetic techniques. Scheme 1 provides a general syntheticscheme for exemplary compounds of the invention utilizing ester A wherethe variables Q, L¹, P, R⁴, n, and R¹ have any of the values describedabove with respect to any of the embodiments, W is a OH or a halogensuch as, but not limited to a Cl, Br, or I, and Alk is a straight orbranched chain alkyl group having from 1-8 carbon atoms. It will beunderstood that the phenolic OH group of A can be replaced with an SHand reacted with a compound where W is a halogen to produce theanalogous S-containing derivative to the compounds shown. The methodsand examples provided below provide syntheses of A bearing differentexemplary R¹ groups. Additional examples for the synthesis of esters offormula A are described in described in WO 2005/086661 and US2006/0004012 which are both hereby incorporated by reference in theirentireties and for all purposes as if fully set forth herein. Furtherrelevant synthetic routes for related compounds are also described in WO2005/086661 and US 2006/0004012. Appropriate starting materials can beprepared by techniques known or apparent to those of skill in the art orthe starting materials may be commercially available. One of skill inthe art will understand that the synthetic routes can be modified to usedifferent starting materials or alternative reagents and that suitableadjustments in conditions (e.g., temperatures, solvents, etc.) can bemade to accomplish the desired transformations. Additionally, one ofskill in the art will recognize that protecting groups may be necessaryfor the preparation of certain compounds and will be aware of thoseconditions compatible with a selected protecting group. Examples of suchprotecting groups include, for example, those set forth in ProtectiveGroups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley &Sons, New York, N.Y., (3rd Edition, 1999). Accordingly, the exemplarymethods and the examples described herein are illustrative of thepresent invention and are not to be construed as limiting the scopethereof.

Scheme 2 shows a general synthetic route that can be used to preparecompounds of formula XV and XVI, and salts thereof. In the compound offormula XIII and XV, Alk is a straight or branched chain alkyl grouphaving from 1 to 8 carbon atoms. Examples of such groups include methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, i-propyl, s-butyl,t-butyl groups, and the like. In some embodiments, Alk is a methyl orethyl group. In the compounds of formula XIII, XV and XVI, R¹ is any ofthe R¹ groups described herein. For example, R¹ may be selected fromcyano, aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³ where R²and R³ have the same values as set forth with respect to any of thecompounds of any of the embodiments set forth herein. In the compoundsof formula XIII, XV and XVI, R⁵ is independently selected from(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro, and p is selectedfrom 0, 1, 2, 3, or 4. In the compounds of formula XIII, XIV, XV, andXVI, R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ are each independentlyselected from hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; m is selected from 1, 2, 3, or 4; n′ isselected from 0, 1, 2, or 3; one of R⁶ and R^(6′) is L¹ or Q, if L¹ is abond, and the others of R⁶ and R^(6′) are independently selected from H,(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro, wherein one of R⁶and one of R^(6′) on adjacent or non-adjacent carbon atoms, or on thesame carbon atom may join together to form a C₅-C₈ cycloalkane ring, ortwo of R⁶ or two of R^(6′), on adjacent or non-adjacent carbon atoms,may join together to form a C₅-C₈ cycloalkane ring, z is selected from1, 2, or 3, L¹ is selected from a bond, (C₁-C₄)alkylene,(C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)), R^(a) is selected fromhydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or (C₂-C₆)heteroalkyl, R^(b)is selected from hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl, and Q isselected from hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl. In the compound of formula XIV, W represents aleaving group such as a halogen like Br or Cl or OH. Coupling of acompound of formula XIV with a compound of formula XIII may beaccomplished using different procedures. For example, when W is ahalogen such as Br, Cl, or I (conveniently synthesized from the othertwo using the Finkelstein reaction as known to those skilled in theart), then a compound of formula XIII may be coupled with a compound offormula XIV by reacting the two in the presence of any appropriate basesuch as, but not limited to, Cs₂CO₃ in an appropriate solvent such as,but not limited to DMF. When W is an OH, then a compound of formula XIIImay be coupled with a compound of formula XIV using an azodicarboxylatesuch as DEAD, TMAD, or DIAD in combination with a suitable phosphinesuch as a trialkylphosphine, a triarylphosphine, analkyldiarylphosphine, or a dialkylarylphosphine. This highly flexibleapproach allows a large number of compounds of formula XV to besynthesized and then converted to compounds of formula XVI by removal ofthe ester functionality. Conversion of a compound of formula XV to acompound of formula XVI may be accomplished by reacting the compound offormula XV with a base such as a metal hydroxide base such as, but notlimited to, LiOH, NaOH, KOH, Ca(OH)₂, or the like. Those skilled in theart will recognize that the carbon atom bonded to R¹ in compounds offormula XIII, XV, and XVI is a chiral center. In accordance with themethod described above, XIII, XV, and XVI may be a mixture of the R andS enantiomers, may be the R enantiomer, or may be the S enantiomer.Therefore, in some embodiments each of the compounds of formula XIII,XV, and XVI are a mixture of the R and S enantiomers. In otherembodiments, each of the compounds of formula XIII, XV, and XVI are theR enantiomer. In other embodiments, each of the compounds of formulaXIII, XV, and XVI are the R enantiomer.

In one aspect, the invention provides a method of synthesizing acompound of formula XV as shown in Scheme 2. The method includes:reacting a compound of formula XIII with a compound of formula XIV toproduce the compound of formula XV, wherein the compounds of formulaXIII, XIV, and XV have the following structures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)alkynyl, or —C(O)NR²R³; R² and R³ are independently selected fromhydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl; optionally, R² and R³ arecombined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogenatom to which they are attached comprising from 0 to 2 additionalheteroatoms selected from N, O, or S; and; R⁵ is independently selectedfrom (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; p isselected from 0, 1, 2, 3, or 4; z is selected from 1, 2, or 3; R^(4′) isindependently selected from substituted (C₁-C₆)alkyl, —R′, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, wherein R′, R″ and R′″ are each independentlyselected from hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; n′ is 0, 1, 2, or 3; m is 1, 2, 3, or 4; oneof R⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the others of R⁶ andR^(6′) are independently selected from H, (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or nitro, wherein one of R⁶ and one of R^(6′) onadjacent or non-adjacent carbon atoms, or on the same carbon atom mayjoin together to form a C₅-C₈ cycloalkane ring, or two of R⁶ or two ofR^(6′), on adjacent or non-adjacent carbon atoms, may join together toform a C₅-C₈ cycloalkane ring; L¹ is selected from a bond,(C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)); R^(a) is selected fromhydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or (C₂-C₆)heteroalkyl; R^(b)is selected from hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; Q isselected from hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; W is a leaving group; and further wherein, thecompounds of formula XIII and XV can be a mixture of compounds havingthe R and S stereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.

In some embodiments, W is selected from OH, a halogen, an OTs, an OMs,or an OTf where OTs represents the tosylate (Ts is p-toluenesulfonyl)OMs represents mesylate (Ms is methanesulfonyl), and OTf representstriflate (Tf is trifluoromethanesulfonyl). In some such embodiments, Wis OH and a phosphine selected from a trialkylphosphine, adialkylarylphosphine, a alkyldiarylphosphine, or a triarylphosphine andan azodicarboxylate are used to react the compound of formula XIII withthe compound of formula XIV. In other such embodiments, W is a halogenselected from Br or Cl, and a base is used to react the compound offormula XXII with the compound of formula XXIII.

In some embodiments, Alk is selected from methyl or ethyl.

In some embodiments, m is 1 or 2.

In some embodiments, n′ is 0

In some embodiments, z is 1.

In some embodiments, the method further includes removing the Alk groupof the compound of formula XV to form a compound of formula XVI or asalt thereof, and the compound of formula XVI has the followingstructure:

wherein the variables have the definitions provided with respect to thecompounds of any of the embodiments of formula XIII, XIV, and XV. Insome such embodiments, the compound of formula XV is reacted in thepresence of a hydroxide base to produce the compound of formula XVI. Insome such embodiments, the hydroxide base is selected from LiOH, NaOH,KOH, or Ca(OH)₂.

5.2.3 Compositions

In another aspect, the invention provides pharmaceutical compositionssuitable for pharmaceutical use comprising one or more compounds of theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. By “pharmaceutically acceptable” it is meant that thecarrier, excipient, or diluent is compatible with the other ingredientsof the formulation and is not deleterious to the recipient thereof.

Composition formulation may improve one or more pharmacokineticproperties (e.g., oral bioavailability, membrane permeability) of acompound of the invention (herein referred to as the active ingredient).

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art. All methodsinclude the step of bringing the active ingredient into association withthe carrier which constitutes one or more accessory ingredients. Ingeneral, the pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition, the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are, water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The pharmaceutical compositions and methods of the invention may furthercomprise other therapeutically active compounds, as noted herein, usefulin the treatment of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

5.2.4 Methods of Use

In another aspect, the invention provides methods of treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound or composition of the invention.

In one embodiment, the disease or condition is type II diabetes.

In another aspect, the present invention provides a method for treatinga disease or condition responsive to the modulation of GPR40 comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound or composition of the invention.

In some embodiments, the disease or condition is selected from the groupconsisting of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

In certain embodiments, the disease or condition is type II diabetes.

In some embodiments, the disease or condition is obesity.

In some embodiments, the disease or condition is hypertension.

In some embodiments of administering the compounds or compositions ofthe invention, the compound or composition is administered orally.

In other embodiments, the compound or composition is administeredparenterally.

In other embodiments, the compound or composition is administered incombination with a second therapeutic agent.

In other embodiments, the second therapeutic agent is an insulinsensitizing agent, such as metformin or a thiazolidinedione, forexample.

In another aspect, the invention provides methods of treating orpreventing a disease or disorder responsive to modulation of GPR40comprising administering to a subject having such a disease or disorder,a therapeutically effective amount of one or more of the subjectcompounds or compositions.

In yet another aspect, the invention provides methods of treating orpreventing a GPR40-mediated condition, disease or disorder comprisingadministering to a subject having such a condition, disease or disorder,a therapeutically effective amount of one or more of the subjectcompounds or compositions.

In yet another aspect, the invention provides methods of modulatingGPR40 comprising contacting a cell with one or more of the subjectcompounds or compositions.

For example, in some embodiments, a cell that constitutively expressesGPR40 is contacted with one or more of the subject compounds orcompositions.

In certain embodiments, a cell to be contacted can be made to express oroverexpress GPR40, for example, by expressing GPR40 from heterologousnucleic acid introduced into the cell or, as another example, byupregulating the expression of GPR40 from nucleic acid endogenous to thecell.

Depending on the disease to be treated and the subject's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the treatment or prevention type II diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome,syndrome X, cardiovascular disease, atherosclerosis, kidney disease,ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy,diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia,hypoglycemia, cancer and edema or other conditions or disordersassociated with GPR40, an appropriate dosage level will generally beabout 0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range, the dosage may be 0.005 to 0.05, 0.05to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, thecompositions are preferably provided in the form of tablets containingfrom 1.0 to 1000 milligrams of the active ingredient, particularly 1.0,3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the diseases or conditions for which compounds of theinvention are useful, including type II diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefore, simultaneously or sequentially with acompound of the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound ofthe invention.

The compounds of the invention may be used in combination with a secondtherapeutic agent such as those described herein. Thus, in someembodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a subject with a disease or condition mediated by GPR40. Insome embodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in theprophylactic treatment of a subject at risk for a disease or conditionmediated by GPR40. In some such embodiments, the components are providedas a single composition. In other embodiments, the compound and thesecond therapeutic agent are provided separately as parts of a kit.

Examples of other therapeutic agents that may be combined with acompound of the invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (a)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andother statins), bile acid sequestrants (e.g., cholestyramine andcolestipol), vitamin B₃ (also known as nicotinic acid, or niacin),vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), fibric acidderivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (b) antithrombotic agents, such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, β-blockers (e.g., atenolol),β-adrenergic agonists (e.g., isoproterenol), ACE inhibitors andvasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride,nitroglycerin and enaloprilat); and (c) anti-diabetic agents such asinsulin and insulin mimetics, sulfonylureas (e.g., glyburide,meglinatide), biguanides, e.g., metformin (GLUCOPHAGE®), α-glucosidaseinhibitors (acarbose), insulin sensitizers, e.g., thiazolidinonecompounds, rosiglitazone (AVANDIA®), troglitazone (REZULIN®),ciglitazone, pioglitazone (ACTOS®) and englitazone, DPP-IV inhibitors,e.g., vildagliptin (Galvus®), sitagliptin (Januvia™), and GLP-I analogs,e.g., exenatide (Byetta®). In some embodiments, a compound of theinvention may be administered along with a DPP-IV inhibitor or a GLP-Ianalog.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.Combinations of a compound of the invention and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

In another aspect, the present invention provides a method formodulating circulating insulin concentration in a subject, comprisingadministering a compound or composition of the invention.

In some embodiments, the insulin concentration is increased.

In other embodiments, the insulin concentration is decreased.

The following examples are offered by way of illustration and are notintended to limit the scope of the invention. Those of skill in the artwill readily recognize a variety of noncritical parameters that could bemodified to yield essentially similar results.

6. EXAMPLES

Unless otherwise stated, all compounds were obtained from commercialsources or were prepared using the methods and experimental proceduresdescribed herein. Various procedures are also set forth in publishedU.S. Patent Application No. 2006/0004012 which is hereby incorporated byreference in its entirety and for all purposes as if set forth herein.The following abbreviations are used to refer to various reagents,solvents, experimental procedures, or analytical techniques that aredescribed in the examples:

ACN Acetonitrile

AcOH Acetic Acid

DCM Dichloromethane

DEAD Diethyl azodicarboxylate

DIBALH Diisobutylaluminum Hydride

DMF N,N′-Dimethyl Formamide

DMSO Dimethyl Sulfoxide

ESI Electrospray Ionization

EtOAc EtOAc

EtOH Ethanol

HPLC High Performance Liquid Chromatography

HSA Human Serum Albumin

i-ProH 2-Propanol

LDA Lithium Diisopropylamide

MeOH Methanol

MS Mass Spectrometry

NBS N-Bromosuccinimide

n-BuLi n-Butyllithium

NMR Nuclear Magnetic Resonance

n-ProH 1-Propanol

PCC Pyridinium Chlorochromate

PDC Pyridinium Dichromate

PPTS Pyridinium p-Toluenesulfonate

t-BuOH t-Butanol

TEA Triethlamine

TFA Trifluoroacetic Acid

THF Tetrahydrofuran

THP Tetrahydropyran

TLC Thin Layer Chromatography

TMAD N,N,N′,N′-Tetramethylazodicarboxamide

SPA Scintilliation Proximity Assay

5-(4-Hydroxy-benzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (M1.1).Condensation with Meldrum's acid was carried out according to the methodof Bigi et. al. (2001) Tetrahedron Lett. 42:5203-5205. A 2 L pear-shapedflask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water(400 mL). The flask was placed in a water bath at 75° C., and Meldrum'sacid (62 g, 430 mmol) was added as a slurry in 400 mL of water. Thereaction mixture was agitated for 2 hours and cooled in an ice bath for2 hours. The product was collected by filtration and rinsed with coldwater. After drying thoroughly, adduct M1.1 was obtained as a fineyellow powder. MS ESI (pos.) m/e: 519.0 (2M+Na). ¹H NMR (500 MHz)(DMSO-d₆) δ 9.75 (br s, 1H); 8.27 (s, 1H); 8.24 (d, 2H, J=10 Hz); 6.98(d, 2H, J=10 Hz); 1.76 (s, 6H).

(+/−)-5-[1-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione(M1.2). An oven-dried 3 L 3-neck flask was equipped with a mechanicalstirrer, a nitrogen inlet, and a nitrogen outlet and placed in aroom-temperature water bath. After purging with nitrogen for 20 minutes,a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) wasadded by cannula. In a separate oven-dried and nitrogen-flushed 500 mLround-bottom flask, compound M1.1 (35 g, 142 mmol) was dissolved inanhydrous THF (350 mL) with gentle warming. The solution of M1.1 wasadded over 15 minutes. Over the course of the addition, the reactionmixture changed to a thick, yellow suspension. After the addition wascomplete, the reaction mixture was stirred for 15 minutes, quenched withaqueous NH₄Cl (0.6 N, 750 mL), and diluted with hexanes (800 mL). Thelayers were separated, and the organic layer was discarded. The aqueouslayer was acidified to pH 2 with saturated aqueous KHSO₄ and extractedwith EtOAc (2×400 mL). The combined extracts were washed with saturatedbrine, dried over MgSO₄, filtered, and concentrated to a light yellowsolid. MS ESI (pos.) m/e: 599.0 (2M+Na). ¹H NMR (500 MHz) (acetone-d₆) δ8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (brs, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s,3H).

(+/−)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (M1.3). A 1 L round-bottomflask was charged with compound M1.2 (37 g), diethyl ketone (160 mL),and water (80 mL). The suspension was heated at reflux for 48 hours.After cooling, the aqueous layer was saturated with NaCl(s) andseparated. The organic layer was dried over MgSO₄, filtered, andconcentrated to a light brown oil, which was crystallized from hotEtOAc:hexanes (1:2). After collecting and drying, the product wasobtained as an off-white powder. MS ESI (pos.) m/e: 205.1 (M+H); 227.1(M+Na). ¹H NMR (500 MHz) (DMSO-d₆) δ 12.2 (s, 1H); 9.27 (s, 1H); 7.12(d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, 1H); 2.54 (m, 2H);1.82 (d, 3H, J=2.4 Hz).

(3S)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (M1.4). A 5 L round-bottomflask was charged with compound M1.3 (66.4 g, 325 mmol) and 2-propanol(1 L) and heated to 70° C. (1S,2R)-1-Amino-2-indanol (46.1 g, 309 mmol)was dissolved in 2-propanol (1 L) with gentle warming. The solution ofamine was added to the dissolved carboxylic acid and the resultingsolution was allowed to cool to room temperature. After 16 hours, thecrystals were collected and dried. The salt was re-suspended in 2 L of2-propanol and dissolved by heating to reflux. After allowing to cool toroom temperature, the salt was collected after 16 hours. A small sampleof the salt was decomposed with aqueous acid and the free carboxylicacid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant:0.1% TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. Thesalt was re-suspended in 1.5 L of 2-propanol and dissolved by heating toreflux. After allowing to cool to room temperature, the salt wascollected after 16 hours. This material was found to have 96% ee bychiral HPLC. This material was suspended in EtOAc (300 mL) and water(100 mL). Saturated aqueous KHSO₄ (100 mL) was added with vigorousmixing. After two clear layers were obtained, the layers were separated,and the aqueous layer was extracted with EtOAc (100 mL). The combinedextracts were washed with saturated brine, dried over MgSO₄, filtered,and concentrated to a light yellow oil, which crystallized on drying invacuo. Compound M1.4 was obtained as an off-white solid.

(3S)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (M1). PhenolM1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treatedwith KHCO₃ (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80mmol) was added, and the reaction was stirred at 40° C. for 14 hours. Anadditional portion of methyl iodide (3 mL, 48 mmol) was added andheating was continued for 24 hours. Potassium salts were removed byfiltration and thoroughly rinsed with acetone. The filtrate wasconcentrated to an oil, which was filtered through a 1 cm plug of silicagel. Elution with 2.5% MeOH in DCM followed by concentration providedphenol M1 as a light yellow oil. MS ESI (pos.) m/e: 219.1 (M+H); 241.1(M+Na). ¹H NMR (500 MHz) (acetone-d₆) δ 8.2 (br s, 1H); 7.20 (d, 2H,J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H); 2.65 (m,2H); 1.78 (d, 3H, J=2.5 Hz).

Ethyl 3-(4-fluoro-phenyl)-3-(4-hydroxy-phenyl)-acrylate (M2.1). Asolution of lithium hexamethyldisilazide (23.1 mL, 1 M in THF) was addedto a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9mmol) in THF (15 mL) in 10 minutes at −78° C. The reaction mixture wasfurther stirred at this temperature for 20 minutes. A solution of(4-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (2 g, 9.2 mmol) in THF(30 mL) was slowly added to the reaction mixture. The reaction mixturewas brought to 0° C. over 5 hours. The reaction mixture was quenchedwith saturated NH₄Cl solution, extracted into EtOAc and washed withdilute NH₄Cl solution. The organic layer was dried over magnesiumsulfate. The solvent was removed under vacuum, and the resulting productwas flash chromatographed on silica gel, giving M2.1 as an oil.

(+/−)-3-(4-Fluoro-phenyl)-3-(4-hydroxy-phenyl)-propionic acid ethylester (M2). A solution of M2.1 (385 mg) in EtOH (12 mL) and EtOAc (10mL) was stirred with 10% Pd—C (50 mg) under a hydrogen atmosphere atroom temperature for 3 hours. The reaction mixture was filtered andconcentrated to provide M2.

6.3 Method 3

Starting from (4-hydroxy-phenyl)-phenyl-methanone, compound M3 wasprepared according to methods analogous to those described in Method 2.

2,2-Dimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-benzylidene]-[1,3]dioxane-4,6-dione(M4.1). Protection of the phenol with dihydropyran was carried out basedon the method described in Miyashita et al. (1977) J. Org. Chem.42:3772. Compound M1.1 (500 g, 2 mol) was dissolved in DCM (4 L).3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followedby PPTS (5 g, 20 mmol). The reaction mixture was then heated at a gentlereflux (3.5 hours). The reaction was concentrated under reduced pressureto ˜2 L of volume. 1 L of acetone was then added, and 2 L of solventwere removed under reduced pressure. 1 L of acetone was added, and 1 Lof solvent was removed under reduced pressure. 0.5 L of acetone wasadded, and 0.5 L of solvent was removed under reduced pressure. Theresulting slurry of very fine, light yellow crystals was filtered andrinsed sequentially with two 500 mL portions of acetone. The product wasdried in a vacuum oven at 50° C. until no further solvent collected inthe traps. Compound M4.1 was obtained as fine, light yellow crystals. MSESI (pos.) m/e: 355.1 (M+Na). ¹H NMR (400 MHz) (DMSO-d₆) δ 8.29 (s, 1H);8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz); 5.67 (m, 1H); 3.70 (m,1H); 3.60 (m, 1H). 1.9-1.5 (m, 12H).

(+/−)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate (M4). A 500mL flask was equipped with a magnetic stir bar, a nitrogen inlet, and anitrogen outlet and placed in a room-temperature water bath. CompoundM4.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF(150 mL). After purging with nitrogen for 30 minutes, a solution ofthiophene-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added bycannula. After the addition was complete, the reaction mixture wasstirred for 1.5 hours and quenched with aqueous NH₄Cl (1 M, 100 mL), anddiluted with EtOAc (100 mL). The aqueous layer was acidified to pH ˜2with concentrated HCl and extracted with EtOAc (150 mL×2). The extractwas washed with brine and concentrated. The residue was dissolved in 100mL of 10:1 DMF:water and heated to 100° C. for 8 hours. The reaction wascooled, diluted with 500 mL water, and extracted with EtOAc (150 mL×3).The organic layer was dried with MgSO₄, filtered, and concentrated on arotary evaporator. The residue was dissolved in MeOH (200 mL), 5 dropsof concentrated H₂SO₄ were added, and the solution was refluxed for 24hours. The solution was concentrated to a residue on a rotary evaporatorand flash column chromatographed with 30% EtOAc/hexanes as the eluant.The fractions were combined and concentrated to afford M4 as a viscousoil.

2-(4-(Benzyloxy)phenyl)-N-(prop-2-ynyl)acetamide (M5.1). A mixture of4-(benzyloxy)phenylacetic acid (20.7 mmol), 1-hydroxybenzotrizolehydrate (37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37mmol), propargylamine (20.7 mmol) and N-methylmorpholine (62 mmol) inDMF (60 mL) were stirred at room temperature overnight. The reactionmixture was diluted with EtOAc (400 mL), washed with 1N HCl, water,saturated Na₂CO₃ solution, and brine, and dried over Na₂SO₄. Afterremoving solvent under reduced pressure, the residue was triturated withDCM. Compound M5.1 was obtained as a white solid after filtration anddrying. LC-MS ESI (pos.) m/e: 280 (M+H).

2-(4-Benzyloxy)benzyl)-5-methyl oxazole (M5.2). A mixture of compoundM5.1 (10.1 mmol) and AuCl₃ (1 mmol) in DCM (100 mL) was stirred at roomtemperature overnight. Additional DCM (100 mL) was added, and thereaction mixture was washed with NaHCO₃ solution and saturated brine.After drying over Na₂SO₄ and concentration under reduced pressure, theresidue was column chromatographed (1:2 EtOAc:hexanes) to obtaincompound M5.2. LC-MS ESI (pos.) m/e: 280 (M+H).

(+/−)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate(M5.3). To a solution of 2-(4-(benzyloxy)benzyl)-5-methyloxazole (M5.2)(3.23 mmol) in THF (25 mL) at −78° C., was added dropwise LDA (4.5mmol). The mixture was stirred for 18 minutes, followed by addition ofethyl bromoacetate (4.5 mmol). It was allowed to warm to roomtemperature for 3 hours, followed by addition of water, which wasextracted with EtOAc. The extract was washed with brine and dried overNa₂SO₄ using standard work up conditions. Column chromatography (1/3EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e:366 (M+H).

(+/−)-Ethyl 3-(4-hydroxyphenyl)-3-(5-methyloxazol-2-yl)propanoate (M5).A mixture of ethyl3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate (M5.3) (2.47mmol) and Pd—C (270 mg) in EtOH was stirred under hydrogen atmosphere atroom temperature for 4 hours. The Pd—C was removed by filtration throughsilica gel eluting with EtOH. After concentration, product M5 wasobtained. MS ESI (pos.) m/e 276 (M+H).

(+/−)(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(M6.1). 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M inTHF, 35 mL, 17.5 mmol) was added to a solution of3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly viasyringe at −78° C. The reaction mixture was stirred at this temperaturefor 3 hours and then quenched with saturated NH₄Cl (aqueous). Themixture was extracted with EtOAc (60 mL×2), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide a colorless oil (3.9 g) as product M6.1, which wasused directly in the next step.

(+/−)-(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(M6.2). PDC (8.5 g, 22.6 mmol) was added to the solution of M6.1 (3.9 g,13.7 mmol) in DCM (100 mL) at 0° C. in several portions. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 6 hours. Silicagel (about 20 g) was added to the reaction mixture and the resultingslurry was filtered through a pad of silica gel to remove most of theinorganic chemicals. The solid was washed with DCM until no furtherproduct remained on the silica gel (monitored by TLC). The combinedorganic solvent was washed with water and saturated brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to provide anoily residue, which was flash chromatographed (silica gel, 0-30% EtOAcin hexane), generating product ketone M6.2 as light yellow oil. MS ESI(pos.) m/e: 319 (M+H).

(Z/E)-Ethyl3-(3,5-difluorophenyl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M6.3). Ethyl (trimethylsilyl)acetate (2.63 g/3.0 mL in 20 mL THF) wasadded to lithium hexamethyldisilazide (1 M in THF, 17.6 mL) at −78° C.slowly via syringe. The mixture was stirred at the same temperature for1 hour, and the solution of ketone M6.2 (4.3 g, 13.5 mmol) in anhydrousTHF (25 mL) was added slowly via syringe. The reaction mixture wasfurther stirred at this temperature for 2 hours. The reactiontemperature was then allowed to rise to −20° C. in 6 hours. The reactionmixture was quenched with saturated NH₄Cl (aqueous) at this temperature,extracted with EtOAc (2×100 mL) and dried over Na₂SO₄. After filtration,the solvent was removed under reduced pressure and M6.3 was obtained aslight yellow oil (including some ethyl (trimethylsilyl)acetate), whichwas used directly in the next step. MS ESI (pos.) m/e: 389 (M+H).

(+/−)-Ethyl 3-(3,5-difluorophenyl)-3-(4-hydroxyphenyl)propanoate (M6). Asolution of olefin M6.3 (5.4 g, 13.5 mmol) in EtOH (80 mL) was stirredwith 10% Pd—C (1.5 g, 1.4 mmol) under a hydrogen atmosphere (provided bya balloon) overnight at room temperature. The reaction mixture wasfiltered through a short silica gel pad and stirred with AcOH (14 mL) atroom temperature for 4 hours. The reaction mixture was concentratedunder reduced pressure to provide a yellow oily residue, which wasre-dissolved in DCM (150 mL) and washed with water, saturated NaHCO₃,water, and brine, and dried over Na₂SO₄. After filtration, the solventwas removed under reduced pressure, and the residue was flashchromatographed (silica gel, 0-40% EtOAc in hexane as eluant). Theproduct M6 was obtained as the (+/−)ethyl ester. MS ESI (pos.) m/e: 307(M+H).

(+/−)-Ethyl 3-(2,4-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate(M7). Compound M7 was prepared by a method analogous to that for M6.

(+/−)-Ethyl 3-(2,5-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate (8).Compound M8 was prepared by a method analogous to that for M6.

(+/−)-Ethyl 3-(2,6-difluoro-phenyl)-3-(4-hydroxy-phenyl) propanoate(M9). Compound M9 was prepared by a method analogous to that for M6.

(+/−)-Ethyl 3-(4-hydroxy-phenyl)-3-(5-methyl-thiophen-2-yl) propanoate(M10). Compound M10 was prepared by a method analogous to that for M6.

(+/−)-Oxazol-2-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(M11.1). 4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol)in THF (0.5 M) was added dropwise to a solution ofoxazole-2-carbaldehyde (5.15 mmol) in THF (8 mL). After it was stirredat room temperature for 2.5 hours, the reaction was quenched with waterand extracted with EtOAc (200 mL). The organic phase was washed withbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was column chromatographed (silicagel, 1:2 EtOAc/hexane). Compound M11.1 was obtained. MS ESI (pos.) m/e:276 (M+H). ¹H NMR (400 MHz) (DMSO-d₆) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz,2H); 7.14 (s, 1H); 6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5Hz, 1H); 5.44 (s, 1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H);1.52-1.60 (m, 4H).

(+/−)-Oxazol-2-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(M11.2). PCC (14.5 mmol, 20% w/w on silica gel) was added to a solutionof M11.1 (2.91 mmol) in DCM (20 mL). After it was stirred at roomtemperature for 1 hour, the reaction mixture was column chromatographed(silica gel, 1:2 EtOAc/hexane). Compound M11.2 was obtained. MS ESI(pos.) m/e: 296.0 (M+23). ¹H NMR (500 MHz) (DMSO-d₆) δ 8.52 (s, 1H);8.43 (d, J=9 Hz, 2H); 7.67 (s, 1H); 7.23 (d, J=9 Hz, 2H); 5.71 (m, 1H);3.74-3.76 (m, 1H); 3.62-3.65 (m, 1H); 1.88-1.91 (m, 2H); 1.81-1.82 (m,1H); 1.59-1.67 (m, 3H).

(E/Z)-Methyl3-(oxazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M11.3). Lithium bis(trimethylsilyl) amide (3.46 mmol, 1 M in THF) wasadded dropwise to a solution of methyl trimethylsilylacetate (3.46 mmol)in THF (5 mL) at −78° C. After it was stirred at −78° C. for 20 minutes,a solution of M11.2 (2.16 mmol) in THF (9 mL) was added dropwise, andthe temperature was maintained at −78° C. for 1.5 hours. The reactionwas quenched with water and extracted with EtOAc. The organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was columnchromatographed (silica gel, 1:1 EtOAc/hexane) and compound M11.3 wasobtained. MS ESI (pos.) m/e 330.1 (M+H).

(+/−)-Methyl3-(oxazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)propanoate(M11.4). A mixture of M11.3 (2.55 mmol) and Pd—C (440 mg) in MeOH wasstirred under hydrogen at room temperature for 30 minutes. The Pd—C wasremoved by filtration through silica gel eluting with EtOAc. Afterconcentration, the residue was column chromatographed (silica gel, 1:1EtOAc/hexane) and compound M11.4 was obtained. MS ESI (pos.) m/e 332.2(M+H).

(+/−)-Methyl 3-(4-hydroxyphenyl)-3-(oxazol-2-yl)propanoate (M11). Amixture of M11.4 (2.1 mmol), p-toluenesulfonic acid monohydrate (0.57mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours.After it was quenched with NaHCO₃ (aqueous) solution, MeOH was removedby rotary evaporator. The residue was extracted with EtOAc, and thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, and filtered through short plug of silica gel. Afterremoving solvent, compound M11 was obtained. MS ESI (pos.) m/e 248.1(M+H). ¹H NMR (500 MHz) (DMSO-d₆) δ 9.04 (s, 1H); 7.99 (s, 1H); 7.14 (s,1H); 7.05 (m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, 1H); 3.57 (s, 1H);3.22-3.27 (m, 1H); 2.89-2.94 (m, 1H).

(1-Methyl-1H-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(M12.1). 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M inTHF, 160 mL, 80 mmol) was added slowly to a solution of1-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) viasyringe at −78° C. The reaction mixture was stirred at this temperaturefor 3 hours and quenched with saturated NH₄Cl (aq). The mixture wasextracted with EtOAc (2×100 mL), and the combined organic extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford M12.1 as a colorless oil (21 g), which was used directly in thenext step.

(1-Methyl-1H-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(M12.2). PDC (36 g, 95.7 mmol) was added to a solution of M12.1 (21 g,72.7 mmol) in DCM (100 mL) at 0° C. in several portions. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 6 hours. Silicagel (75 g) was added to the reaction mixture, and the resulting slurrywas filtered through a pad of silica gel. The solid was washed with DCM(200 mL). The filtrate was washed with water and saturated brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give anoily residue, which was flash chromatographed (silica gel, 0-30% EtOAcin hexane) to afford ketone M12.2 as yellow solid (16 g). ¹H NMR (500MHz) (CDCl₃) δ 8.33-8.35 (m, 2H); 7.10-7.29 (m, 4H); 5.56 (t, J=3.0 Hz,1H); 4.08 (s, 3H); 3.85-3.90 (m, 1H); 3.61-3.65 (m, 1H); 2.03 (m, 1H);1.90-1.91 (m, 2H); 1.69-1.74 (m, 2H); 1.61-1.64 (m, 1H).

(Z/E)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M12.3). A solution of lithium hexamethyldisilazide (1 M in THF, 64 mL)was added slowly to a stirred solution of ethyl (trimethylsilyl)acetate(9.9 g, 61.5 mmol) and ketone M12.2 (16 g, 55.9 mmol) in anhydrous THF(60 mL) via syringe at −78° C. The reaction mixture was stirred at thistemperature for 2 hours. The reaction temperature was allowed to rise to−20° C. over 6 hours. The reaction mixture was quenched with saturatedNH₄Cl (aq) at this temperature, extracted with EtOAc (2×150 mL), anddried over Na₂SO₄. After filtration, the solvent was removed underreduced pressure to afford M12.3 as a colorless oil (21 g, includingsome ethyl (trimethylsilyl)acetate), which was used directly in the nextstep. LC-MS ESI (pos.) m/e: 357 (M+H).

(+/−)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)propanoate(M12.4). A solution of olefin M12.3 (21 g, 55.9 mmol) in EtOH (200 mL)was stirred with 10% Pd—C (2.1 g, 2 mmol) under a hydrogen atmosphere(provided by a balloon) at room temperature overnight. The reactionmixture was filtered through a silica gel pad and concentrated toprovide protected ester M12.4 as an off-white oil (21 g), which was useddirectly in the next step. LC-MS ESI (pos.) m/e: 359 (M+H).

(+/−)-Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(M12.5). TFA (21 mL) was added to a solution of protected ester M12.4(21 g) in dry DCM (210 mL) with caution at 0° C. The mixture was broughtto room temperature over 4 hours. The reaction mixture was concentratedunder reduced pressure to provide a yellow oily residue, which wasre-dissolved in DCM (200 mL) and washed with water, saturated NaHCO₃,water and brine, and dried over Na₂SO₄. After filtration, the solventwas removed under reduced pressure, and the product was crystallized inEtOAc-hexane. The mother liquid was concentrated and flashchromatographed (silica gel, 50% EtOAc in hexane as eluant). Theproduct, (±)-ethyl3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (M12.5) wasobtained as a colorless crystal (combined yield 11 g). LC-MS ESI (pos.)m/e: 275 (M+H). ¹H NMR (500 MHz) (CDCl₃) δ 9.28 (s, 1H); 6.98-7.00 (m,3H); 6.65-6.77 (m, 3H); 4.41 (dd, J=9.0, 3.0 Hz, 1H); 3.96 (q, J=7.0,2H); 3.39 (s, 3H); 3.19 (dd, J=16.0, 7.0 Hz, 1H); 2.78 (dd, J=16.0, 6.5Hz, 1H); 1.80 (t, J=7.0 Hz, 3H).

(S)-Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(M12). Racemic compound M12.5 was separated on a preparatory chiral HPLCwith CHIRALPAK AD column, using 11% i-PrOH in hexane as eluant. Eluantcontaining the peak with greater retention time was concentrated andcompound M12 was obtained as colorless crystals. The enantiomer of M12was also obtained. The absolute configuration was assigned by analogy toother GPR40 agonist compounds.

Methyl ester (M13.2). Compound M13.1 (5.5 g, 12.16 mmol, prepared asdescribed in US 2006/0004012 which is hereby incorporated by reference)was dissolved in 100 mL of EtOAc and quinoline (2 mL, 1.093 g/mL, 16.93mmol) was added. Nitrogen was bubbled through the solution for 5minutes. 500 mg of Lindlar's catalyst was added, and a hydrogen balloonwas attached. After 8 hours, the mixture was filtered through a plug ofsilica with EtOAc. The organic layer was washed with 2 N HCl (aq) (2×50mL), saturated NaHCO₃ (aq) (1×50 mL), brine (1×50 mL) and dried withMgSO₄. The organic layer was filtered and concentrated under reducedpressure. The material was chromatographed on silica with 10%EtOAc/hexane to afford M13.2 (5.1 g, 11.22 mmol) as a colorless oil. MSESI (pos.) m/e: 455.0 (M+H)⁺.

Aldehyde (M13.3). Alkene M13.2 (5.1 g, 11.22 mmol) was dissolved in 100mL of 4:1 (1,2-dioxane/water), and 2,6-lutidine (2.61 mL, 0.920 g/mL,22.44 mmol) was added. Next, 1.2 g of a 3.4% OsO₄ in t-BuOH (0.22 mmol)solution was added dropwise over 5 minutes. NaIO₄ (9.6 g, 44.88 mmol) in25 mL of water was added. The internal reaction temperature did not riseabove 30° C. After 8 hours at room temperature, the reaction mixture wasdiluted with 500 mL of DCM, the layers were separated, and the organiclayer was washed with 0.5 M HCl_((aq)) (2×50 mL), saturated NaHCO₃ (aq)(1×50 mL), 5% sodium sulfite (aq) (1×50 mL), and brine. The organiclayer was dried with Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was flashed on silica with 30% EtOAc/hexanes toafford M13.3 (4.0 g, 9.09 mmol) as a yellow oil. MS ESI (pos.) m/e:443.4 (M+H)⁺.

Acid (M13.4). Aldehyde M13.3 (2.32 g, 5.25 mmol) was dissolved in 20 mLof ACN. To this was added KH₂PO₄ (178 mg, 1.31 mmol) in 5 mL of water.The solution was cooled to −5° C. and 30% H₂O₂ (aq) (714 mg, 6.30 mmol)was added. NaClO₂ (712 mg, 7.88 mmol) was dissolved in 5 mL of water andadded via syringe pump over 3 hours while maintaining a temperaturebelow 0° C. After the addition of the NaClO₂ solution, the mixture wasstirred for 1 hour. 300 mL of DCM was added, and the pH of the aqueouslayer was adjusted to 2 with 2 N HCl (aq). The aqueous layer wasextracted with DCM (2×100 mL), and the combined organic extracts werewashed with 5% sodium sulfite (aq) (1×50 mL), and brine. The organiclayer was dried with NaSO₄, filtered, and concentrated under reducedpressure. The residue was chromatographed on silica with 50%EtOAc/hexanes to afford M13.4 (2.12 g, 4.62 mmol) as a colorless oil. MSESI (pos.) m/e: 459.3 (M+H)⁺.

Amide (M13.5). Acid M13.4 (6.0 g, 13.1 mmol) was dissolved in 100 mL ofDCM. To this was added 1-hydroxybenzotriazole hydrate (3.7 g, 27.5mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbondiimide hydrochloride(5.0 g, 26.2 mmol), and 2 M ammonia in n-PrOH (14 mL, 26.2 mmol). Thereaction was stirred for 8 hours and diluted with 500 mL of EtOAc. Theorganic layer was washed with 2N HCl (aq) (2×75 mL), NaHCO₃ (aq) (1×75mL), and brine (1×75 mL) and dried with MgSO₄ and filtered. The organiclayer was concentrated under reduced pressure, and the residue wasflashed through silica with 25% EtOAc/DCM. The combined fractions wereconcentrated under reduced pressure to afford M13.5 (5.3 g, 11.5 mmol)as a colorless oil.

(S)-3-(2-Methyl-2H-1,2,4-triazol-3-yl)-3-[4-(4′-trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-propionicacid (M13.6). Amide M13.5 (6.48 g, 14.2 mmol) was dissolved in 7 mL ofN,N-dimethylformamide dimethyl acetal (119.17 MW, 0.894 g/mL, 52.6mmol). The solution was gradually heated to 80° C. over 30 minutes. Themixture was allowed to cool to 35° C., and the sample was concentratedunder reduced pressure. The residue was dissolved in 20 mL of AcOHfollowed by careful addition of methylhydrazine (5 mL, 0.866 g/mL, 94.0mmol) over 5 minutes (the acid/base exotherm was used to run thereaction). The temperature increased to 65° C., and an oil bath at 80°C. was used to finish the reaction. The total heating time was 45minutes. The reaction was allowed to come to room temperature, and wasdiluted with 500 mL of DCM. The organic layer was washed with water(3×100 mL), brine (1×100 mL), dried with Na₂SO₄, filtered, andconcentrated to a residue. The material was flashed on silica with 10%ACN/DCM to afford methyltriazole M13.6 (4.3 g, 8.7 mmol) as a yellowoil. MS ESI (pos.) m/e: 496.5 (M+H)⁺.

(S)-Methyl3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate (M13).Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL ofEtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 gof palladium on carbon (5 wt. %, wet contains 50% water) was added, anda hydrogen balloon was attached. After 8 hours, the mixture was filteredthrough a plug of silica with 10% MeOH in EtOAc. The organic layer wasconcentrated under reduced pressure and partitioned between ACN (100 mL)and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). TheACN layer was concentrated under reduced pressure to afford (S)-methyl3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate M13(1.30 g, 4.99 mmol) as a colorless oil. MS ESI (pos.) m/e: 262.4 (M+H)⁺.

Methylamide (M14.1). Acid M13.4 (6.0 g, 13.1 mmol), prepared asdescribed above, was dissolved in 100 mL of DCM. To this mixture wasadded 1-hydroxybenzotriazole hydrate (3.7 g, 27.5 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbondiimide hydrochloride (5.0 g,26.2 mmol), and 2 M methylamine in THF (14 mL, 26.2 mmol). The reactionwas stirred for 8 hours, diluted with 500 mL of EtOAc, and the organiclayer was washed with 2N HCl (aq) (2×75 mL), NaHCO₃ (aq) (1×75 mL),brine (1×75 mL) and dried with MgSO₄ and filtered. The organic layer wasconcentrated under reduced pressure, and the residue was flashed throughsilica with 15% EtOAc/DCM. The combined fractions were concentratedunder reduced pressure to afford M14.1 (4.2 g, 11.5 mmol) as a colorlessoil. MS ESI (pos.) m/e: 472.3 (M+H)⁺.

(S)-3-(1-Methyl-1H-tetrazol-5-yl)-3-[4-(4′-trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-propionicacid (M14.2). Methylamide M14.1 (2.15 g, 4.59 mmol) was dissolved in 50mL of ACN. NaN₃ (900 mg, 13.8 mmol) was added followed by the dropwiseaddition of Tf₂O (5.2 g, 18.4 mmol). The temperature rose to 34° C. Thereaction was stirred for 12 hours and diluted with 250 mL of DCM. Theorganic layer was washed with NaHCO₃ (aq) (2×50 mL), brine (1×50 mL) anddried with MgSO₄ and filtered. The organic layer was concentrated underreduced pressure, and the residue was flashed through silica with 15%EtOAc/DCM. The combined fractions were concentrated under reducedpressure to afford methyltetrazole M14.2 (1.52 g, 3.07 mmol) as acolorless oil. MS ESI (pos.) m/e: 497.4 (M+H)⁺.

(S)-Methyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)propanoate(M14). Methyltetrazole M14.2 (413 mg, 0.833 mmol) was dissolved in 5 mLof EtOAc and nitrogen was bubbled through the solution for 5 minutes.Palladium on carbon (200 mg, 5 wt. %, wet contains 50% water) was added,and a hydrogen balloon was attached. After 8 hours, the mixture wasfiltered through a plug of silica with 10% MeOH in EtOAc. The organiclayer was concentrated under reduced pressure and partitioned betweenACN (10 mL) and hexane (5 mL). The ACN layer was washed with hexane (4×5mL). The ACN layer was concentrated under reduced pressure to afford(S)-methyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)propanoate(M14) (203 mg, 0.775 mmol) as a colorless oil.

Formic hydrazide (M15.1). Acid M13.4 (10 mmol) is dissolved in 100 mL ofDCM. To this is added 1-hydroxybenzotriazole hydrate (20 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbondiimide hydrochloride (20 mmol),and formic hydrazide (12 mmol). The reaction is stirred for 8 hours anddiluted with 500 mL of EtOAc. The organic layer is washed with 2 N HCl(aq) (2×75 mL), NaHCO₃ (aq) (1×75 mL), and brine (1×75 mL) and driedwith MgSO₄ and filtered. The organic layer is concentrated under reducedpressure, and the residue is purified on silica. The combined fractionsare concentrated under reduced pressure to afford M15.1.

Thiadiazole (M15.2). Formic hydrazide M15.1 (9 mmol) is dissolved in THF(100 mL) and Lawesson's Reagent (18 mmol) is added. The mixture isstirred for 24 hours and then is concentrated to a residue. The residueis purified on silica gel to afford M15.2.

Thiadiazole Phenol (M15). Thiadiazole M15.2 (8 mmol) is dissolved inEtOAc (100 mL) and Pd/C (18 mmol) is added under nitrogen atmosphere. Ahydrogen balloon is attached and the mixture is stirred for 24 hours andthen is filtered and concentrated to a residue. The residue is purifiedon silica gel to afford M15.

A mixture of phenol (0.18 mmol),6-halomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (0.2mmol) or another benzyl chloride or benzyl bromide compound, and cesiumcarbonate (0.27 mmol) in DMF (2 mL), was/is stirred at room temperatureovernight. The reaction mixture was/is diluted with water and extractedinto DCM. The separated DCM layer was/is washed with water. The residueobtained after concentration was/is dissolved into THF and MeOH (1 mLeach) and treated with 2 M NaOH solution (0.45 mL, 0.9 mmol). Theresulting solution was/is further stirred for 16-48 hours at roomtemperature. The reaction mixture was/is concentrated, and the residuewas/is dissolved in a mixture of DMF/ACN (1:4, 5 mL) containing TFA (67μL, 0.9 mmol). This solution was/is filtered and purified by preparatoryHPLC. The solvent was/is evaporated by freeze-drying to provide thedesired product generally as a white amorphous solid.

6.16 Example 1

(S)-3-(1-Methyl-1H-imidazol-2-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (1). Compound 1 was obtained from compound 1.1 (M12) (see Method12) using the general procedure A. MS ESI (neg.) M/E: 445 (M−H). ¹HNMR(DMSO-d₆) δ 7.65 (s, 1H), 7.6 (s, 1H), 7.3 (overlapping m, 2H), 7.20 (d,2H), 7.1 (d, 1H), 7.0 (d, 2H), 5.0 (s, 2H), 4.85 (m, 1H), 3.8 (s, 1H),3.1 (dd, 1H), 1.6 (s, 4H), 1.2 (s, 12H).

6.17 Example 2

(S)-3-(2-Methyl-2H-[1,2,4]triazol-3-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (2). Compound 2 was obtained from compound 2.1 (M13) by followingthe general procedure A. MS ESI (neg.) M/E: 446 (M−H). ¹HNMR (DMSO-d₆) δ7.75 (s, 1H), 7.2 (m, 2H), 7.12 (s, 2H), 7.08 (d, 1H), 6.85 (d, 2H), 4.9(s, 2H), 4.5 (m, 1H), 3.6 (s, 3H), 3.1 (dd, 1H), 2.7 (dd, 1H), 1.55 (s,4H), 1.15 (s, 12H).

6.18 Example 3

This example illustrates the preparation of(S)-3-(3-methyl-3H-1,2,3-triazol-4-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (3).

1-methyl-1H-1,2,3-triazole (3.1). A mixture of2-(trimethylsilyl)-2H-1,2,3-triazole (179 mmol), MeI (179 mmol), andTBAF on silica gel (16.3 mmol) in ACN (200 mL), was refluxed for 4hours. After cooling to room temperature, the mixture was concentratedwith silica gel and chromatographed (silica gel, 5:95 MeOH/DCM). Thefractions containing product were collected, concentrated, and distilledunder vacuum to give desired product 1.1 (7.5 g, 90 mmol, b.p.=97° C. at3 mmHg). MS ESI (pos.) m/e 83.9 (M+H).

(4-(Benzyloxy)phenyl)(3-methyl-3H-1,2,3-triazol-4-yl)methanol (3.2). Asolution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was addeddropwise to a solution of 3.1 (1.29 g, 15.5 mmol) in THF (75 mL) at −40°C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehyde wasadded at −40° C., and the reaction was warmed to room temperature. Thereaction was quenched saturated NH₄Cl (aq) after 3 hours of stirring andthen extracted with EtOAc. The organic phase was washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue 3.2 was used in the next reactionwithout further purification. MS ESI (pos.) m/e 296.2 (M+H).

(4-(Benzyloxy)phenyl)(3-methyl-3H-1,2,3-triazol-4-yl)methanone (3.3).Dess-Martin periodinane (8 g, 19 mmol) was added to a solution of 3.2(˜15.5 mmol) in DCM (80 mL). After 1 hour, the reaction mixture wasconcentrated with silica gel and chromatographed (silica gel, 1:2EtOAc/hexane) to obtain compound 3.3 (4.3 g, 14.7 mmol). MS ESI (pos.)m/e: 294.1 (M+H).

Ethyl 3-(4-(benzyloxy)phenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)acrylate(3.4). To a solution of lithium bis(trimethylsilyl)amide (22 mmol, 1 min THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 3.3 (14.7 mmol) inTHF (50 mL) was added dropwise, and the reaction was maintained at −78°C. for 4 hours. The reaction was quenched with saturated NH₄Cl (aq) andwarmed to room temperature. The mixture was extracted with EtOAc (500mL), dried over anhydrous sodium sulfate, filtered, and concentratedwith silica gel under reduced pressure. The residue was chromatographed(silica gel, 1:1 EtOAc/hexane) to afford compound 3.4 (5.1 g, 14 mmol).MS ESI (pos.) m/e 364.1 (M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)propanoate(3.5). 3.4 was dissolved in EtOH and stirred with Pd—C (1.48 g, 0.7mmol) under hydrogen at room temperature for 3 hours. The Pd—C wasremoved by filtration through celite with EtOAc as eluant. Afterconcentration, the residue was chromatographed (silica gel, 1:1EtOAc/hexane) to afford compound 3.5 (3.28 g, 12 mmol). MS ESI (pos.)m/e 276.1 (M+H).

(S)-ethyl3-(4-hydroxyphenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)propanoate (3.6).Racemic compound 3.5 (3.28 g, 12 mmol) was separated on asemi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 30%i-PrOH hexane as eluant. Eluant containing the peak with less retentiontime was concentrated and compound 3.6 (1.5 g, 5.45 mmol) was obtainedas off-white solid. The absolute configuration was assigned by analogyto other GPR40 agonist compounds. MS ESI (pos.) m/e 276.1 (M+H).

(S)-3-(3-methyl-3H-1,2,3-triazol-4-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (3). A mixture of 3.6 (0.15 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.18mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at roomtemperature for 16 hours. To the reaction mixture was added LiOH inwater (1 mL, 1N solution), and the resulting mixture was stirred at 50°C. for 3 hours. The mixture was filtered and purified by reverse phaseHPLC to give 3 (26 mg, 0.06 mmol) after lyophilization. MS ESI (pos.)m/e 448.3 (M+H). ¹H NMR (500 MHz) (CDCl₃) δ 7.95 (1H, s), 7.71 (1H, s),7.33-7.36 (2H, m), 7.20 (1H, dd, J=7.9, 1.5 Hz), 7.07 (2H, d, J=8.5 Hz),6.97 (2H, d, J=8.9 Hz), 4.98 (2H, s), 4.51-4.55 (1H, m), 3.86 (3H, s),3.11-3.17 (1H, m), 3.01-3.07 (1H, m), 1.72 (4H, s), 1.31 (6H, s) 1.30(6H, s).

6.19 Example 4

This example illustrates the preparation of(S)-3-(1-methyl-1H-imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (4).

(1-Methyl-1H-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(4.1). 4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (110 mL, 0.5M in THF, 55 mmol) was added dropwise to a solution of1-methyl-1H-imidazole-5-carbaldehyde (4.7 g, 50 mmol) in THF (790 mL) at−78° C. After stirring −78° C. for 2 hours, the reaction was quenchedwith saturated NH₄Cl (aq) and warmed to room temperature. The mixturewas extracted with EtOAc (500 mL), and the organic phase was washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give 14 g of the crude product4.1, which was used in the next reaction without further purification.

(1-Methyl-1H-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(4.2). Dess-Martin periodinane (21 g, 50 mmol) was added to a solutionof 4.1 (14 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, thereaction mixture was concentrated with silica gel and chromatographed(silica gel, 1:2 EtOAc/hexane) to provide compound 4.2 (3.3 g, 11.5mmol). MS ESI (pos.) m/e: 287.1 (M+H).

Ethyl3-(1-methyl-1H-imidazol-5-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(4.3). To a solution of lithium bis(trimethylsilyl)amide (6.8 mmol, 1 Min THF) was added ethyl trimethylsilylacetate (6.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 4.2 (5.9 mmol) in THF(20 mL) was added dropwise. The reaction was maintained at −78° C. for 3hours and at −45° C. for 2 hours. The reaction was quenched withsaturated NH₄Cl (aq) at 0° C. and warmed to room temperature. Themixture was extracted with EtOAc (500 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to affordcrude 4.3 (2.49 g). MS ESI (pos.) m/e 357.2 (M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-5-yl)propanoate (4.4).The crude 4.3 was dissolved in EtOH (50 mL), stirred with Pd—C (1.48 g,0.7 mmol) under hydrogen at room temperature for 60 hours. The Pd—C wasremoved by filtration through celite with EtOAc as eluant. Afterconcentration, the residue was treated with TFA (2 mL) in dry DCM (20mL) at room temperature for 2 hours. The reaction mixture wasconcentrated then redissolved in DCM, washed with water, washed withsaturated NaHCO₃, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane)to afford compound 4.4 (700 mg, 2.6 mmol). MS ESI (pos.) m/e 275.2(M+H).

(S)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-5-yl)propanoate(4.5). Racemic compound 4.4 (680 mg, 2.5 mmol) was separated on asemi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 15%i-PrOH in hexane as eluant. Eluant containing the peak with lessretention time was concentrated and compound 4.5 (300 mg, 1.1 mmol) wasobtained as off-white solid. The absolute configuration was assigned byanalogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).

(S)-3-(1-methyl-1H-imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (4). A mixture of 4.5 (0.15 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.18mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at roomtemperature for 16 hours. To the reaction mixture was added LiOH inwater (1 mL, 1N solution), and the reaction was stirred at 50° C. for 3hours. The mixture was filtered and purified by reverse phase HPLC togive 4 (35 mg, 0.08 mmol) after lyophilization. MS ESI (pos.) m/e 447.3(M+H). ¹H NMR (500 MHz) (CDCl₃) δ 8.64 (1H, s), 7.59 (1H, s), 7.33-7.36(2H, m), 7.20 (1H, dd, J=7.9, 1.8 Hz), 7.08 (2H, d, J=8.5 Hz), 6.98 (2H,d, J=8.5 Hz), 4.98 (2 H, s), 4.53 (1H, m), 3.57 (3H, s), 2.96-3.06 (2H,m), 1.71 (4H, s), 1.31 (6H, s), 1.30 (6H, s).

6.20 Example 5

This example illustrates the preparation of(S)-3-(oxazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (5).

Oxazol-5-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol (5.1).4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (120 mL, 0.5 M inTHF, 60 mmol) was added dropwise to a solution of oxazole-4-carbaldehyde(4.85 g, 50 mmol) in THF (90 mL) at −78° C. After stirring at −78° C.for 21 hours, the reaction was quenched with saturated NH₄Cl (aq) andwarmed to room temperature. The mixture was extracted with EtOAc (500mL), the organic phase was washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give 17 g of the crude product 5.1, which was used in thenext reaction without further purification.

Oxazol-5-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (5.2).Dess-Martin periodinane (25 g, 60 mmol) was added to a solution of 5.1(17 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, the reactionmixture was concentrated with silica gel and chromatographed (silicagel, 1:2 EtOAc/hexane) to obtain compound 5.2 (5.74 g, 21 mmol). MS ESI(pos.) m/e: 274.1 (M+H).

Ethyl 3-(oxazol-5-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(5.3). To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1 Min THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 5.2 (21 mmol) in THF(60 mL) was added dropwise and the reaction was maintained at −78° C.for 1.5 hours. The reaction was quenched saturated NH₄Cl (aq) and warmedto room temperature. The mixture was extracted with EtOAc (500 mL), theorganic phase was washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated with silica gel under reducedpressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane)to afford compound 5.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2 (M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (5.4). TFA (10 mL)was added to a solution of 5.3 (14 mmol) in dry DCM (100 mL) and stirredat room temperature for 2 hours. To the reaction mixture was slowlyadded solid NaHCO₃ with stirring. The reaction was then washed withsaturated NaHCO₃ (2×), dried over Na₂SO₄, and concentrated under reducedpressure. The residue was then re-dissolved in EtOH, stirred with Pd—C(1.48 g, 0.7 mmol) under hydrogen at room temperature for 14 hours. ThePd—C was removed by filtration through celite with EtOAc as eluant.After concentration, the residue was chromatographed (silica gel, 1:1EtOAc/hexane) to afford compound 5.4 (1.3 g, 5 mmol). MS ESI (pos.) m/e262.1 (M+H).

(S)-ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (5.5). Racemiccompound 5.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiralCHIRALCEL OJ-H column (30×250 mm), using 20% i-PrOH in hexane as eluant.Eluant containing the peak with greater retention time was concentratedand compound 5.5 (620 mg, 2.38 mmol) was obtained as off-white solid.The absolute configuration was assigned by analogy to other GPR40agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).

(S)-3-(Oxazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (5). A mixture of 5.5 (0.1 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.12mmol) and cesium carbonate (0.15 mmol) in DMF (2 mL) was stirred at roomtemperature for 3 hours. To the reaction mixture was added LiOH in water(1 mL, 1N solution), and the reaction was stirred at 50° C. for 3 hours.The mixture was filtered and purified by reverse phase HPLC to give 5(12 mg, 0.03 mmol) after lyophilization. MS ESI (pos.) m/e 434.2 (M+H).¹H NMR (500 MHz) (CDCl₃) δ 7.94 (s, 1H); 7.31-7.41 (m, 3H); 7.22 (d,J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 6.87 (s, 1H); 4.99 (s, 2H); 4.58(t, J=7.9 Hz, 1H); 3.14 (dd, J=16.5, 7.6 Hz, 1H); 2.99 (dd, J=16.5, 7.6Hz, 1H); 1.72 (s, 4H); 1.31 (s, 12H).

6.21 Example 6 Synthesis of(S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (6)

(E)-4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)acrylate (6.2).Potassium carbonate (21 g, 152 mmol) was added to a mixture of4-hydroxycinnamic acid 6.1 (6.25 g, 38.1 mmol) and p-methoxy benzylchloride (10.35 mL, 76 mmol) in DMF (100 mL). The mixture was stirred at80° C. for five hours. After cooling, the mixture was poured into water(700 mL). The solid was collected by filtration, washed with water anddried to give 6.2 (15 g). MS ESI (pos.) m/e: 405 (M+H). ¹HNMR (CDCl₃) δ7.68 (d, 1H), 7.47 (d, 2H), 7.38 (m, 4H), 6.95 (m, 6H), 6.35 (d, 1H),5.20 (s, 2H), 5.03 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H).

4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)-4-nitrobutanoate (6.3).1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to 6.2 (5 g,12.4 mmol) in nitromethane (20 mL). The mixture was stirred at roomtemperature for 3 hours, at 50° C. for 3 hours, and at 100° C. for 8hours. Nitromethane was removed under vacuum and the crude product waspurified by flash chromatography to give 6.3 (4.5 g). MS ESI (pos.) m/e:466 (M+H). ¹HNMR (CDCl₃) δ 7.37 (d, 2H), 7.19 (d, 2H), 7.12 (d, 2H),6.92 (m, 6H), 5.01 (s, 2H), 4.97 (s, 2H), 4.68 (m, 1H), 4.59 (m, 1H),3.96 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 2.77 (m, 2H).

4-Methoxybenzyl3-(4-(4-methoxybenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoate (6.4).Triethylamine (1 mL) was added to a mixture of 6.3 (1.89 g, 4.1 mmol),vinyl bromide (32.5 mL, 1.0 M solution in THF) and 1,4-phenylenediisocyanate (2.3 g, 14.35 mmol). The mixture was stirred at 80° C. for8 hours. After cooling, the solid was removed from the mixture byfiltration, and the filtrate was concentrated and purified by flashchromatography to give 6.4 (3 g). MS ESI (pos.) m/e: 474 (M+H). ¹HNMR(CDCl₃) δ 8.28 (d, 1H), 7.37 (d, 2H), 7.18 (m, 4H), 6.92 (m, 6H), 6.07(d, 1H), 5.02 (s, 2H), 4.97 (s, 2H), 4.59 (t, 1H), 3.84 (s, 3H), 3.82(s, 3H), 3.33 (dd, 1H), 3.00 (dd, 1H).

Ethyl 3-(4-hydroxyphenyl)-3-(isoxazol-3-yl)propanoate (6.5). TFA (10 mL)was added to 6.4 (940 mg) in DCM (10 mL). The mixture was stirred atroom temperature for 1.5 hours. TFA and DCM were removed under vacuum,and the residue was treated with EtOH (50 mL). The insoluble solid wasremoved by filtration. To the filtrate was added concentrated sulfuricacid (2 drops). The mixture was stirred at 80° C. overnight. Afterconcentration, the crude product was purified by flash chromatography togive 6.5 (410 mg). MS ESI (pos.) m/e: 262 (M+H). ¹HNMR (CDCl₃) δ 8.29(d, 1H), 7.12 (d, 2H), 6.76 (d, 2H), 6.10 (d, 1H), 4.56 (t, 1H), 4.10(q, 2H), 3.27 (dd, 1H), 2.97 (dd, 1H), 1.19 (t, 3H). The racemiccompound 6.5 was separated into two enantiomers 6.6 and 6.7 using chiralpreparative AD-H column (8% IPA/92% hexanes). The stereochemistry of 6.6and 6.7 was assigned arbitrarily.

(S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (6). Cesium carbonate (14 mg, 0.042 mmol) was added into a mixtureof 6.6 (10 mg, 0.038 mmol) and6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (11mg, 0.038 mmol) in DMSO (0.5 mL). The mixture was stirred at roomtemperature for 2 hours and at 35° C. for 4 hours. After cooling, themixture was treated with EtOAc (5 mL) and brine (5 mL). The organiclayer was separated, washed with brine twice, dried and concentrated.The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5mL) and NaOH (0.05 mL, 10N). The mixture was stirred at room temperaturefor 4 hours. The organic solvent was blown away by nitrogen and theaqueous was acidified by HCl (0.18 mL, 3N). The aqueous was extractedwith DCM. The organic layer was dried, concentrated and purified byflash chromatography to give 6 (15 mg). MS ESI (pos.) m/e: 434 (M+H).¹HNMR (CDCl₃) δ 8.30 (d, 1H), 7.35 (m, 2H), 7.19 (m, 3H), 6.96 (d, 2H),6.09 (d, 1H), 4.97 (s, 2H), 4.57 (t, 1H), 3.37 (dd, 1H), 2.99 (dd, 1H),1.71 (s, 4H), 1.30 (s, 12H).

6.22 Example 7

(R)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (7). Compound 7 was synthesized using the procedure above forpreparing Example 6 using compound 6.7. MS ESI (pos.) m/e: 434 (M+H).¹HNMR (CDCl₃) δ 8.30 (d, 1H), 7.35 (m, 2H), 7.19 (m, 3H), 6.96 (d, 2H),6.09 (d, 1H), 4.97 (s, 2H), 4.57 (t, 1H), 3.37 (dd, 1H), 2.99 (dd, 1H),1.71 (s, 4H), 1.30 (s, 12H).

6.23 Example 8 Synthesis of(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (8)

(2,3-Dihydro-1H-inden-5-yl)methanol (11) To a solution of 8.1 (1.0 g,6.17 mmol) in THF was slowly dripped BH₃.THF (30 mL, 1.0 M in THF) at 0°C. The reaction mixture was stirred at this temperature for 2 hours andthen quenched with water. The mixture was poured into water, andextracted with EtOAc. The crude product was chromatographed on a silicagel column to afford the alcohol 8.2. ¹HNMR (DMSO-d₆) δ 7.17-7.15 (m,2H), 7.05 (d, 1H, J=7.57 Hz), 5.04 (t, 1H, J=5.87 Hz), 4.45 (d, 2H,J=5.63 Hz), 2.84 (m, 4H), 2.01 (m, 2H).

(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (8) This compound was prepared by procedure analogous to thatdescribed in Example 16 starting with intermediate 8.2 which wasconverted to chloride 8.3 and then reacted with the imidazole phenol M12shown in the reaction scheme and followed be removal of the ester group.MS ESI (pos.) m/e: 377.2 (M+H). ¹HNMR (MeOH-d₄) δ 7.52-7.48 (d, 2H),7.26 (s, 1H), 7.23-7.15 (m, 4H), 7.02 (d, 2H, J=8.80 Hz), 5.04 (s, 2H),4.95 (m, 1H), 3.84 (s, 3H), 3.37 (m, 1H), 3.19 (m, 1H), 2.89 (t, 4H,J=7.34 Hz), 2.08 (m, 2H).

6.24 Example 9

(R/S)-3-Pyrimidin-5-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (9). Compound 79.1 was prepared using the procedure in Method 12used to prepare M12.5 using pyrimidine-5-carboxaldehyde in place of1-methyl-2-imidazolecarboxaldehyde. Compound 9 was obtained fromcompound 9.1 by following the general procedure A. MS ESI (neg.) M/E:443 (M−H). ¹HNMR (DMSO-d₆) δ 8.9 (s, 1H), 8.7 (s, 2H), 7.25 (m, 4H), 7.1(d, 1H), 6.8 (d, 1H), 4.9 (s, 2H), 4.3 (m, 1H), 3.1 (dd, 1H), 3.0 (dd,1H), 1.55 (s, 4H), 1.15 (s, 12H).

6.25 Example 10

Compound 10.1 was reduced to 10.2 using a procedure very similar to thatdescribed in JOC, 43, (1978), 2167. 10.2 was converted to 10.3 by simplytreating it with thionyl chloride at room temperature.

(S)-3-(1-Methyl-1H-imidazol-2-yl)-3-[4-(5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (10). Compound 10 was obtained from compound M12 and 10.3 byfollowing the general procedure A. MS ESI (neg.) M/E: 389 (M−H). ¹HNMR(DMSO-d₆) δ 7.6 (s, 1H), 7.5 (s, 1H), 7.2 (d, 2H), 7.1-6.9 (overlappingsignals, 5H), 4.9 (s, 2H), 4.8 (m, 1H), 3.7 (s, 1H), 3.3 (dd, 1H), 3.0(dd, 1H).

6.26 Example 11

(S)-3-(1-Methyl-1H-tetrazol-5-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (11). Compound 11 was obtained from compound M14 by following thegeneral procedure A. MS ESI (neg.) M/E: 447 (M−H). ¹HNMR (DMSO-d₆) δ 7.3(2s, 2H), 7.2 (d, 2H), 7.1 (d, 1H), 7.05 (d, 1H), 6.85 (d, 2H), 4.9 (s,2H), 4.6 (m, 1H), 3.8 (s, 3H), 3.2 (dd, 1H), 2.8 (dd, 1H), 1.55 (s, 4H),1.1 (s, 12H).

6.27 Example 12

12.1 12

(S)-3-Oxazol-2-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (12). Compound 12 was obtained from compound 12.1 (resolved M11) byfollowing the general procedure A. MS ESI (neg.) M/E: 432 (M−H). ¹HNMR(MeOH-d₄) δ 7.8 (s, 1H), 7.3 (m, 2H), 7.2 (m, 3H), 7.1 (s, 1H), 6.95 (d,2H), 5.0 (s, 2H), 4.6 (m, 1H), 3.8 (s, 3H), 3.25 (dd, 1H), 2.9 (dd, 1H),1.7 (s, 4H), 1.3 (s, 12H).

6.28 Examples 13 and 14 Synthesis of carboxylic acids (13) and (14)

Aldehyde (13.3). The benzyl bromide 13.1 (10.24 g, 32.5 mmol) and4-hydroxybenzaldehyde 13.2 (3.97 g, 32.5 mmol) were dissolved in 300 mLof acetone. K₂CO₃ (8.9 g, 65 mmol) was then added. After 18 hours atroom temperature, the reaction mixture was filtered through a plug ofsilica and concentrated afford 13.3 (11.4 g, 32 mmol, 98% yield). MS ESI(pos.) m/e: 357 (M+H)⁺.

Alcohol (13.5). 3-Mercapto-4-methyl-1,2,4-triazole (468 mg, 4.07 mmol)was dissolved in 100 mL of THF and the solution was cooled to −78° C.under a nitrogen atmosphere. 2.5 M n-BuLi (4.07 mL, 10.18 mmol) wasadded over one minute. After 5 minutes, a solution of aldehyde 13.3(1.45 g, 4.07 mmol) in 8 mL THF was added over 5 minutes. After 2 hours,the reaction mixture was poured onto 100 mL saturated NH₄Cl_((aq))solution and subsequently diluted with 100 mL EtOAc. The organic layerwas washed with water (1×250 mL), brine (1×250 mL) and dried with MgSO₄.The organic layer was filtered and concentrated under reduced pressure.The crude material was flashed through silica with 40% EtOAc/Hex toafford 13.5 (1.44 g, 3.06 mmol, 75% yield). MS ESI (pos.) m/e: 472(M+H)⁺.

Alcohol (13.6). Alcohol 13.5 (1.44 g, 3.06 mmol) was dissolved in 50 mLof 4:1 THF/water. To this mixture was added NaNO₂ (422 mg, 6.12 mmol)followed by dropwise addition of concentrated HNO₃ (0.38 mL, 6.12 mmol).The reaction was stirred for 1 hour and then was diluted with 400 mL ofEtOAc. The organic layer was washed with NaHCO_(3(aq)) (2×150 mL), brine(1×150 mL), dried with MgSO₄, and filtered. The organic layer wasconcentrated under reduced pressure to afford 13.6 (1.34 g crudematerial). MS ESI m/e: 440 (M+H)⁺.

Ketone (13.7). Alcohol 13.6 (1.34 g crude) was dissolved in 50 mL of THFand Dess-Martin (15 mL, 0.3 M, 4.5 mmol) was added. After 18 hours, themixture was diluted with EtOAc and then washed with NaSO₃(aq) (2×150mL), brine (1×150 mL), and dried with MgSO₄ and filtered. The organiclayer was concentrated under reduced to afford ketone 13.7 (1.34 gcrude). MS ESI (pos.) m/e: 438 (M+H)⁺.

Ethyl ester (13.8). LHMDS (3 mL, 1 M, 3.00 mmol) was diluted with 25 mLof THF and cooled to −78° C. Then, ethyltrimethylsilylacetate (0.47 mL,2.57 mmol) was added dropwise and the mixture was allowed to warm to−50° C. over 1.5 hours. The mixture was cooled to −78° C. and the ketone13.7 (934 mg, 2.14 mmol) was added in 20 mL THF. After 1 hour, themixture was poured onto 100 mL saturated NH₄Cl (aq) solution andsubsequently diluted with 250 mL of EtOAc. The organic layer wasseparated and washed with brine (1×150 mL). The organic layer was driedwith MgSO₄, filtered and concentrated under reduced pressure to afford13.8 as a crude material. MS ESI (pos.) m/e: 508 (M+H)⁺.

1,2,4-(4-Methyltriazole) (13.9). The ester 13.8 (˜2.14 mmol) wasdissolved in 50 mL of EtOAc then wet Pd/C (1.77 g) was added. Themixture was flushed with nitrogen, and a hydrogen balloon was attached.After 14 hours, the mixture was filtered through a small plug of silica,and the material was concentrated under reduced pressure. The residuewas prepared by HPLC C18 chromatography to afford phenol 13.9 (400 mg,1.45 mmol) as a white solid. The material was dissolved in MeOH and theenantiomers were separated on a Chiral AD-H column. 180 mg of eachenantiomer was obtained. MS ESI (pos.) m/e: 276 (M+H)+.

Carboxylic Acids (13 and 14). Benzyl bromide 13.10 (58 mg, 0.19 mmol)and phenol 13.9 (either of the separated enantiomers) (47 mg, 0.17 mmol)were dissolved in DMF (3 mL) and treated with Cs₂CO₃ (277 mg, 0.86mmol). The reaction was stirred at room temperature for 16 hours andthen diluted with EtOAc (50 mL) and washed with water (1×50 mL), brine(1×50 mL), then dried with MgSO₄, filtered, and concentrated to aresidue. The residue was dissolved in THF/MeOH/water, 3:1:1, and 10equivalents 2N LiOH_((aq)) was added. The reaction was stirred for 12hours and then concentrated to a residue. The residue was purified byHPLC C18 column chromatography (ACN/Water/TFA). Eluent containingcompound 13 or 14 (depending on the enantiomer of 13.9 used) waslyophilized to afford a white solid (40 mg, 52%). ¹H NMR (500 MHz)(DMSO_(D6)) δ 8.50 (s, 1H); 7.35 (d, J=1.6 Hz, 1H); 7.32 (d, J=8.8 Hz,1H); 7.16-7.19 (m, 3H); 6.96 (d, J=9.4 Hz, 2H); 4.97 (s, 2H); 4.56 (dd,J=6.1, 9.4 Hz, 1H); 3.44 (s, 3H); 3.24 (dd, J=9.4, 17.2 Hz, 1H); 2.84(dd, J=6.1, 17.2 Hz, 1H); 1.64 (s, 4H); 1.24 (s, 6H); 1.23 (s, 6H). MSESI (pos.) m/e: 448.1 (M+H)⁺.

6.29 Example 15 Synthesis of3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (15)

4-Methoxybenzyl3-(4-(4-methoxybenzyloxy)phenyl)-3-(4,5-dihydroisoxazol-3-yl)propanoate(15.1). Ethylene was bubbled into a mixture of 6.3 (235 mg, 0.5 mmol,see Example 6) in benzene (2 mL) for 20 minutes. Phenyl isocyanate (0.22mL, 2 mmol) and TEA (3 drops) were then added. The mixture was stirredat room temperature for 2 days. The solid was removed by filtration andwashed by benzene. The filtrate was concentrated and purified by flashchromatography to give 15.1 (200 mg). MS ESI (pos.) m/e: 476 (M+H).¹HNMR (CDCl₃) δ 7.37 (d, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 6.92 (m, 6H),5.05 (dd, 2H), 4.98 (s, 2H), 4.25 (m, 2H), 4.10 (t, 1H), 3.84 (s, 3H),3.82 (s, 3H), 3.24 (dd, 1H), 2.79 (m, 3H).

3-(4,5-Dihydroisoxazol-3-yl)-3-(4-hydroxyphenyl)propanoic acid (15.2).TFA (1 mL) was added to 15.1 (100 mg) in DCM (1 mL). The mixture wasstirred at room temperature for 40 hours. TFA and DCM were removed undervacuum, and the residue was treated with EtOH (50 mL). The insolublesolid was removed by filtration. The filtrate was concentrated to give15.2 (50 mg), which was used in the next step without furtherpurification. MS ESI (pos.) m/e: 236 (M+H).

3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (15). Cesium carbonate (108 mg, 0.33 mmol) was added into a mixtureof 15.2 (25 mg, 0.11 mmol) and6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (76mg, 0.27 mmol) in DMSO (1 mL). The mixture was stirred at 45° C. for 3hours. After cooling, the mixture was treated with EtOAc (5 mL) andbrine (5 mL). The organic layer was separated, washed with brine twice,dried and concentrated. The crude product was treated with THF (1 mL),MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10N). The mixture wasstirred at room temperature for 4 hours. The organic solvent was blownaway by nitrogen, and the aqueous layer was acidified by HCl (0.18 mL,3N). The aqueous layer was extracted with DCM. The organic layer wasdried, concentrated and purified by flash chromatography to give 15 (15mg). MS ESI (pos.) m/e: 436 (M+H). ¹NMR (CDCl₃) δ 7.35 (m, 2H), 7.19 (m,3H), 6.96 (d, 2H), 4.97 (s, 2H), 4.28 (m, 2H), 4.07 (t, 1H), 3.28 (dd,1H), 2.79 (m, 3H), 1.71 (s, 4H), 1.30 (s, 12H).

6.30 Example 16 Synthesis of(S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (16)

Starting material 16.1 was prepared according to the published procedureof Endo, Y. et al. (J. Med. Chem. 1998, 41, 1476-1496). To a solution of16.1 (150 mg, 0.78 mmol) in CHCl₃ (5 mL) was added SOCl₂ (3 mL). Thesolution was heated at reflux for 3 hours. The solvent and excess SOCl₂were removed under reduced pressure. The residue, crude 16.2 was pumpedto dryness for half an hour under vacuum and redissolved in DMF (5 mL).Cs₂CO₃ (1.3 g, 4 mmol), and the imidazole phenol M12 shown in thereaction scheme (0.21 g, 0.77 mmol) were added as shown in the reactionscheme. The reaction mixture was left to stir at room temperatureovernight, quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column with 20-80% EtOAc/hexane toafford the ester 16.3.

(S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (16). The ester 16.3 was dissolved in THF (3 mL) and MeOH (3 mL).To the solution was added 2N NaOH aqueous (3 mL), and the reaction wasleft overnight. The mixture was neutralized with AcOH (0.5 mL),filtered, and directly purified with C₁₈ reverse-phase HPLC eluting with10-90% ACN/H₂O containing 0.1% TFA. The product fractions werelyophilized to afford 16. MS ESI (pos.) m/e: 419.2 (M+H). ¹HNMR(MeOH-d₄) δ 7.52 (d, 2H, J=10.76 Hz), 7.37 (s, 1H), 7.22 (d, 2H, J=8.80Hz), 7.09 (d, 1H, J=7.83 Hz), 7.03 (d, 3H, J=8.56 Hz), 5.03 (s, 2H),4.95 (m, 1H), 3.84 (s, 3H), 3.37 (m, 1H), 3.19 (m, 1H), 2.76 (t, 2H,J=6.36 Hz), 1.82 (m, 2H), 1.69 (m, 2H), 1.27 (s, 6H).

6.31 Example 17 Synthesis of(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (17)

1-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanol (17.2)To a solution of 17.1 (1.0 g, 4.34 mmol) in MeOH (20 mL) was added NaBH₄(0.41 g, 10.8 mmol) at 0° C. The reaction was left at room temperatureovernight. The solvent was then removed under reduced pressure. Theresidue was extracted with EtOAc/H₂O. The crude product waschromatographed with 0-20% EtOAc/hexane to afford 17.2. ¹HNMR (DMSO-d₆)δ 7.26 (d, 1H), 7.24 (d, 1H), 7.06 (dd, 1H), 4.99 (d, 1H), 4.64 (m, 1H),1.64 (s, 4H), 1.29 (d, 3H), 1.24 (m, 12H).

(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (17) To a mixture of the imidazole phenol compound M12 shown in thereaction scheme (200 mg, 0.73 mmol), 17.2 (370 mg, 1.59 mmol), andtributylphosphine (0.54 mL, 2.19 mmol) in THF (8 mL) was addedN,N,N′,N′-tetramethylazodicarboxamide (TMAD) (0.38 g, 2.21 mmol) afterbubbling with Ar for 2 minutes. The reaction mixture was stirred at roomtemperature overnight, quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column to afford the ester 17.3. Theester was hydrolyzed by procedure analogous to that described forExample 16. MS ESI (pos.) m/e: 461.2 (M+H). ¹HNMR (MeOH-d₄) δ 7.50-7.46(m, 2H), 7.29-7.26 (m, 2H), 7.14-7.10 (m, 3H), 6.91 (d, 2H, J=8.81 Hz),5.34 (m, 1H), 4.90 (m, 1H), 3.81 (ss, 3H), 3.31 (m, 1H), 3.16 (m, 1H),1.69 (s, 4H), 1.58 (d, 3H, J=6.35 Hz), 1.31 (m, 1H), 1.27-1.16 (m, 12H).

6.32 Example 18 Synthesis of(S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (18)

6-(Bromomethyl)-4,4-diethyl-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene(18.2) Starting material 18.1 was prepared according to the publishedprocedure of Kim, C. et al. (Tetrahedron. Lett. 1994, 35 (19),3017-3020). A mixture of 18.1 (0.5 g, 2.17 mmol), NBS (0.58 g, 3.25mmol), and dibenzoyl peroxide (53 mg) in CCl₄ (10 mL) was heated atreflux for 5 hours. The reaction was cooled, and the precipitate wasfiltered out. The solvent was removed providing crude 18.2, which wasused directly in the next step.

(S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (18) Compound 18 was prepared using a procedure analogous to thatdescribed in Example 16 starting with the imidazole phenol compound M12shown in the reaction scheme and 18.2. MS ESI (pos.) m/e: 475.1 (M+H).¹HNMR (MeOH-d₄) δ 7.47 (dd, 2H, J=11.7, 2.2 Hz), 7.32 (d, 1H, J=8.1 Hz),7.09-7.20 (m, 4H), 7.01-6.94 (m, 2H), 5.03 (s, 2H), 4.95-4.88 (m, 1H),3.83 (s, 3H), 3.34 (m, 1H), 3.14 (m, 1H), 1.73-1.52 (m, 6H), 1.59-1.47(m, 2H), 1.24 (s, 6H), 0.68 (t, 6H, J=7.3 Hz).

6.33 Example 19

(S)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-ynoicacid (19). Compound 19.1 is obtained by the procedure of Example 1 setforth in US 2006/0004012 which is hereby incorporated by reference.Compound 19.1 is reacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of Example 3 setforth in US 2006/0004012 which is hereby incorporated by reference.

6.34 Example 20

(R)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-ynoicacid (20). By changing the resolving agent used in Example 19 to(1R,2S)-1-amino-2-indanol, compound 20.1 is obtained by the procedure ofExample 1 set forth in US 2006/0004012 which is hereby incorporated byreference. Compound 20.1 is reacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of Example 3 setforth in US 2006/0004012 which is hereby incorporated by reference.

6.35 Example 21

Methyl(3R)-3-(4-(((4′-(trifluoromethyl)-1,1′-biphenyl-3-yl)methyl)oxy)phenyl)-4-hexynoate(21.1). Compound 20.1 is reacted with 3-(4-trifluoromethylphenyl)-benzylchloride (obtained by the procedure of Example 2 set forth in US2006/0004012 which is hereby incorporated by reference) by following themethod of Example 3 set forth in US 2006/0004012 which is herebyincorporated by reference.

(R)-4-(Dimethylamino)-4-oxo-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)butanoicacid (21). Compound 21 is converted to the title compound following theprocedure of Example 22.

6.36 Example 22

Methyl(3S)-4-(dimethylamino)-4-oxo-3-(4-(((4′-(trifluromethyl)-1,1′-biphenyl-3-yl)methyl)oxy)phenyl)butanoate(22.1). Acid M13.4 (3.5 g, 7.64 mmol) was dissolved in 50 mL of DCM. Tothis mixture was added 1-hydroxybenzotriazole hydrate (2.17 g, 16.04mmol), N-(3-methylaminopropyl)-N′-ethylcarbondiimide hydrochloride (2.93g, 15.28 mmol), and 2 M dimethylamine in THF (7.7 mL, 15.28 mmol). Thereaction was stirred for 8 hours and diluted with 400 mL of EtOAc. Theorganic layer was washed with 2N HCl_((aq)) (2×50 mL), NaHCO_(3(aq))(1×50 mL), and brine (1×50 mL), dried with MgSO₄, and filtered. Theorganic layer was concentrated under reduced pressure, and the residuewas flashed through silica with 15% EtOAc/DCM. The combined fractionswere concentrated under reduced pressure to afford 22.1 (3.4 g, 7.03mmol) as a colorless oil.

(S)-Methyl 4-(dimethylamino)-3-(4-hydroxyphenyl)-4-oxobutanoate (22.2).Dimethylamide 22.1 (2.1 g, 4.23 mmol) was dissolved in 50 mL of EtOAc,and nitrogen was bubbled through the solution for 5 minutes. 1 g ofpalladium on carbon (5 wt. %, wet contains 50% water) was added, and ahydrogen balloon was attached. After 8 hours, the mixture was filteredthrough a plug of silica with 10% MeOH in EtOAc. The organic layer wasconcentrated under reduced pressure and partitioned between ACN (100 mL)and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). TheACN layer was concentrated under reduced pressure to afford (S)-methyl4-(dimethylamino)-3-(4-hydroxyphenyl)-4-oxobutanoate 22.2 (1.0 g, 3.98mmol) as a colorless oil. MS ESI (pos.) m/e: 252.4 (M+H)⁺.

(S)-4-(Dimethylamino)-4-oxo-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)butanoicacid (22). The phenol 22.2 (315 mg, 1.26 mmol) is dissolved in 5 mL ofDMF and 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) (1.38 mmol) is added followed by cesiumcarbonate (600 mg, 1.88 mmol). The reaction is stirred for 14 hours anddiluted with 250 mL of EtOAc. The organic layer is washed with 1N HCl(aq) (50 mL), saturated NaHCO₃ (aq) (50 mL), and brine (2×50 mL). Theorganic layer is dried with MgSO₄, filtered, and concentrated underreduced pressure. The residue is dissolved in 15 mL THF and 0.111 N NaOH(aq) (16 mL, 1.78 mmol) and MeOH (10 mL) is added. The solution isstirred for 8 hours and concentrated to remove the organic solvent. Theslurry is diluted with water (50 mL) and DCM (300 mL). The mixture isadjusted with 2 N HCl (aq) to a pH of 2 and then extracted with DCM(3×75 mL). The combined organic layers are dried with Na₂SO₄ andconcentrated under reduced pressure. The residue is purified by flashchromatography to yield compound 22.

6.37 Example 23

(S)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(thiophen-2-yl)propanoicacid (23). The racemate of compound 23.1 (obtained by the procedure ofExample 52 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 23.1. Compound 23.1 is reactedwith 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of example 3 setforth in US 2006/0004012 which is hereby incorporated by reference toobtain compound 23.

6.38 Example 24

(R)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(thiophen-2-yl)propanoicacid (24). The racemate of compound 24.1 (obtained by the procedure ofExample 52 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 24.1. Compound 24.1 is reactedwith 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of example 3 setforth in US 2006/0004012 which is hereby incorporated by reference.

6.39 Example 25

(R)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(thiazol-2-yl)propanoicacid 25). The racemate of compound 25.1 (obtained by the procedure ofExample 53 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 25.1. Compound 25.1 is reactedwith 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of Example 3 setforth in US 2006/0004012 which is hereby incorporated by reference toobtain compound 25.

6.40 Example 26

(S)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(thiazol-2-yl)propanoicacid (26). The racemate of compound 26.1 (obtained by the procedure ofExample 53 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 26.1. Compound 26.1 is reactedwith 6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of example 3 setforth in US 2006/0004012 which is hereby incorporated by reference toobtain the title compound.

6.41 Example 27

3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1,3,4-thiadiazol-2-yl)propanoicacid (27). Compound M15 is separated by chiral HPLC using methods knownto those skilled in the art to provide compound 27.1. Compound 27.1 isreacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of Example 3 setforth in US 2006/0004012 which is hereby incorporated by reference toobtain ester 27.2. Ester 27.2 is converted to compound 27 using themethods described herein.

6.42 Example 28

3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1,3,4-thiadiazol-2-yl)propanoicacid (28). Compound M15 is separated by chiral HPLC using methods knownto those skilled in the art to provide compound 28.1. Compound 28.1 isreacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) by following the method of Example 3 setforth in US 2006/0004012 which is hereby incorporated by reference toobtain ester 28.2. Ester 28.2 is converted to compound 28 using themethods described herein.

6.43 Example 29

(R/S)-3-Pyridin-4-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (29). Compound 29.1 was prepared using the procedure in Method 12used to prepare M12.5 using pyridine-4-carboxaldehyde in place of1-methyl-2-imidazolecarboxaldehyde. Compound 29 is obtained fromcompound 29.1 by following the general procedure A.

6.44 Example 30

(R/S)-3-[4-(8,8-Diethyl-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-3-pyridin-4-yl-propionicacid (30). Compound 30 is obtained from compound 29.1 and 18.2 byfollowing the general procedure A.

6.45 Example 31 Synthesis of(R)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (31)

(R)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (31). Compound 31 was obtained from compound 32.2 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 459 (M−H). ¹HNMR (500 MHz,CDCl₃, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J=10Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, 1H J=10 Hz), 3.06 (ddd,2H, J=5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32 (s, 6H), 1.31 (s, 6H).

6.46 Example 32 Synthesis of(S)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (32)

Compound 32.1 was prepared using the procedure of Example 45.2 set forthin US 2006/0004012 which is hereby incorporated by reference. 32.2 and32.3 were separated from racemic material 32.1 using a prep chiral ADcolumn using 10% isopropanol in hexane as eluent. Both compounds(R)-ethyl 3-(4-fluorophenyl)-3-(4-hydroxyphenyl)propanoate 32.2 (thefirst peak on AD column, shorter retention time) and (S)-ethyl3-(4-fluorophenyl)-3-(4-hydroxyphenyl)propanoate 32.3 (the second peakon AD column, longer retention time) were obtained as white solid.

(S)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (32). Compound 32 was obtained from compound 32.3 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 459 (M−H). ¹HNMR (500 MHz,CDCl₃, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J=10Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, 1H J=10 Hz), 3.06 (ddd,2H, J=5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32 (s, 6H), 1.31 (s, 6H).

6.47 Example 33

(R)-Methyl5-methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoate(33.2). The racemate of compound 33.1 (obtained by the procedure ofExample 33 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 33.1. A mixture of compound 33.1(0.18 mmol),6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (0.2mmol; available from Maybridge) and cesium carbonate (0.27 mmol) in DMF(4 mL) is stirred at room temperature overnight. The reaction mixture isdiluted with water and extracted into EtOAc. The separated organic layeris washed with brine and dried over sodium sulfate. After evaporation ofthe solvent, the residue is purified by column chromatography (silicagel; EtOAc/hexane) to yield compound 33.2.

(R)-5-Methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoicacid (33). A mixture of compound 33.2 (0.15 mmol) and sodium hydroxide(0.8 mmol) in water (1 mL) and EtOH (3 mL) is stirred at roomtemperature overnight. EtOH is removed under reduced pressure, and theremaining solution acidified with 1N HCl to pH 3-5 and then diluted withEtOAc (70 mL), washed with saturated brine, dried over anhydrous Na₂SO₄,concentrated under reduced pressure, and purified by columnchromatography (silica gel; 1:9 MeOH/DCM) to yield compound 33.

6.48 Example 34

(S)-Methyl5-methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoate(34.2). The racemate of compound 34.1 (obtained by the procedure ofExample 33 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 34.1. A mixture of compound 34.1(0.18 mmol),6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (0.2mmol; available from Maybridge) and cesium carbonate (0.27 mmol) in DMF(4 mL) is stirred at room temperature overnight. The reaction mixture isdiluted with water and extracted into EtOAc. The separated organic layeris washed with brine and dried over sodium sulfate. After evaporation ofthe solvent the residue is purified by column chromatography (silicagel; EtOAc/hexane) to yield compound 34.2.

(S)-5-Methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoicacid (34). Compound 34 is prepared from 34.2 by the procedure of Example33.

6.49 Example 35

(S)-Methyl3-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-5-enoate(35.2). The racemate of compound 35.1 (obtained by the procedure ofExample 34 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 35.1. Compound 35.1 is reactedwith 6-bromomethyl-1,2,3,4-tetrahydro-naphthalene (prepared using theprocedure of Example 103) by the procedure of Example 33 to yieldcompound 35.2.

(S)-3-(4-((5,6,7,8-Tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-5-enoicacid (35). Compound 35 is prepared from compound 35.2 by the procedureof Example 33.

6.50 Example 36

(R)-Methyl3-(4-((5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-5-enoate(36.2). The racemate of compound 36.1 (obtained by the procedure ofExample 34 set forth in US 2006/0004012 which is hereby incorporated byreference) is separated by chiral HPLC using methods known to thoseskilled in the art to provide compound 36.1. Compound 36.1 is reactedwith 6-bromomethyl-1,2,3,4-tetrahydro-naphthalene by the procedure ofExample 33 to yield compound 36.2.

(R)-3-(4-((5,6,7,8-Tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-5-enoicacid (36). Compound 36 is prepared from compound 36.2 using theprocedure of Example 33.

6.51 Example 37

37.1 37.2

(S)-Methyl3-(1H-pyrrol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)methoxy)phenyl)propanoate(37.2). Compound 37.1 is prepared from(S)-3-amino-3-(4-hydroxyphenyl)propanoic acid (available from Chem-ImpexIntl, Inc.) using the procedure of Example 57 set forth in US2006/0004012 which is hereby incorporated by reference. Alkylationaccording to the procedure of Example 33 provides the title compound37.2.

(S)-3-(1H-Pyrrol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (37). Compound 37 is prepared from 37.2 by the procedure of Example33.

6.52 Example 38

(R)-Methyl3-(1H-pyrrol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)methoxy)phenyl)propanoate(38.2). Compound 38.1 is prepared from(R)-3-amino-3-(4-hydroxyphenyl)propanoic acid (available from Chem-ImpexIntl, Inc.) using the procedure of Example 57 set forth in US2006/0004012 which is hereby incorporated by reference. Alkylationaccording to the procedure of Example 33 provides the title compound38.2.

R)-3-(1H-Pyrrol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (38). Compound 38 is prepared from 38.2 by the procedure of Example33.

6.53 Example 39

(R)-Methyl3-(1H-pyrazol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)methoxy)phenyl)propanoate(39.2). The racemate of 39.1 (obtained by the procedure of Example 58set forth in US 2006/0004012 which is hereby incorporated by reference)is separated by chiral HPLC using methods known to those skilled in theart to provide compound 39.1. Compound 39.2 is prepared from 39.1 by theprocedure of Example 33.

(R)-3-(1H-Pyrazol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (39). Compound 39 is prepared from compound 39.2 by the procedureof Example 33.

6.54 Example 40

(S)-Methyl3-(1H-pyrazol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)methoxy)phenyl)propanoate(40.2). The racemate of 40.1 (obtained by the procedure of Example 58set forth in US 2006/0004012 which is hereby incorporated by reference)is separated by chiral HPLC using methods known to those skilled in theart to provide compound 40.1. Compound 40.2 is prepared from 40.1 by theprocedure of Example 33.

(S)-3-(1H-Pyrazol-1-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (40). Compound 40 is prepared from compound 40.2 by the procedureof Example 33.

6.55 Example 41

(S)-3-(1-methyl-1H-pyrazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,5,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (41). The racemate of compound 41.1 (obtained as a mixture ofregioisomers by the procedure of Example 63 set forth in US 2006/0004012which is hereby incorporated by reference) is separated by chiral HPLCusing methods known to those skilled in the art to provide compound41.1. Compound 41.1 is reacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) to give a mixture of regioisomeric productswhich are separated and hydrolyzed by following the method of Example 63set forth in US 2006/0004012 which is hereby incorporated by reference.

6.56 Example 42

(R)-3-(1-methyl-1H-pyrazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (42). The racemate of compound 42.1 (obtained as a mixture ofregioisomers by the procedure of Example 63 set forth in US 2006/0004012which is hereby incorporated by reference) is separated by chiral HPLCusing methods known to those skilled in the art to provide compound42.1. Compound 42.1 is reacted with6-bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene(available from Maybridge) to give a mixture of regioisomeric productswhich are separated and hydrolyzed by following the method of Example 63set forth in US 2006/0004012 which is hereby incorporated by reference.

6.57 Example 43

Benzyl 6-phenoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (43.2). Toa mixture of compound 43.1 (1.0 g, 3.54 mmol) (43.1 is preparedaccording to the procedure of Fisher, M. J. et al. (Example 39 of U.S.Pat. No. 5,618,843 which is hereby incorporated by reference herein inits entirety and for all purposes as if specifically set forth herein),phenol (0.49 g, 5.21 mmol), and tri-n-butylphosphine (1.62 mL, 6.57mmol) in THF (20 mL) is added TMAD (1.14 g, 6.63 mmol) after bubbling Arfor 3 minutes. The reaction mixture is stirred at room temperatureovernight, quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column to afford compound 43.2.

(3S)-3-(4-Methyl-4H-1,2,4-triazol-3-yl)-3-(4-((6-phenoxy-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (43) This compound is made following a procedure analogous to thatof Example 45 below to afford compound 43.

6.58 Example 44

(S)-Methyl3-(4-methyl-4H-1,2,4-triazol-3-yl)-3-(4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)phenyl)propanoate(44.2). Boronic acid 44.1 is reacted with 13.9 (resolved using chiralchromatography as known to those skilled in the art) using the procedureof Example 42 set forth in US 2006/0004012 which is hereby incorporatedby reference. Isolation and purification of the crude product providesester 44.1.

(S)-3-(4-Methyl-4H-1,2,4-triazol-3-yl)-3-(4-(5,6,7,8-tetrahydronaphthalen-2-yloxy)phenyl)propanoicacid (44). A solution of 44.2 in THF/MeOH (1:1, 2 mL), is treated with2N NaOH aqueous solution (1 mL) and stirred overnight at roomtemperature. The reaction mixture is acidified with aqueous 2N HCl andextracted with EtOAc to obtain 44, which is purified by preparativeHPLC, eluting with 5˜95% ACN in water containing 0.1% TFA.

6.59 Example 45

Benzyl 6-methoxy-5,6,7,8-tetrahydronaphthalene-2-carboxylate (45.2).Starting material 45.1 is prepared according to the procedure of Fisher,M. J. et al. (Example 39 of U.S. Pat. No. 5,618,843 which is herebyincorporated by reference in its entirety and for all purposes as isspecifically set forth herein). To a solution of 45.1 (1.0 g, 3.54 mmol)in THF (20 mL), is added NaH (170 mg, 4.25 mmol, 60% in mineral oil) at0° C. 30 Minutes later, MeI (0.33 mL, 5.34 mmol) is added, and thereaction is left at room temperature overnight, quenched with saline,extracted with EtOAc, and purified on a silica gel column to afford theester 45.2.

(6-Methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (45.3) To asuspension of LAH (0.26 g, 6.83 mmol) in THF (20 mL) is added 45.2 (1.0g, 3.37 mmol) at 0° C. The reaction mixture is heated to reflux for 2hours, is then cooled and quenched with saline. The mixture is filtered,extracted with EtOAc, and chromatographed on a silica gel column toafford the alcohol 45.3.

(3S)-Methyl3-(4-((6-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)propanoate(45.4) To a mixture of 45.3 (210 mg, 1.09 mmol), compound 13.9 (200 mg,0.73 mmol) (resolved using chiral chromatography as known to thoseskilled in the art), and tri-n-butylphosphine (0.54 mL, 2.19 mmol) inTHF (8 mL) is added TMAD (0.38 g, 2.21 mmol) after bubbling Ar for 2minutes. The reaction mixture is stirred at room temperature overnight,quenched with saline, extracted with EtOAc, and chromatographed on asilica gel column to afford compound 45.4.

(3S)-3-(4-((6-Methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)propanoicacid (45). A solution of 45.4 in THF/MeOH (1:1, 2 mL), is treated with2N NaOH aqueous solution (1 mL) and stirred for overnight at roomtemperature. The reaction mixture is acidified with aqueous 2N HCl andextracted with EtOAc to obtain 45, which is purified by preparativeHPLC, eluting with 5-95% ACN in water containing 0.1% TFA.

6.60 Example 46

Napthalenecarboxylic acid, 5,6,7,8-tetrahydro-4-hydroxy-ethyl ester(46.2). The 2-napthalenecarboxylic acid,5,6,7,8-terahydro-4-hydroxy-ethyl ester is formed according to themethod of Kasibhatla et al. (J. Med. Chem., 44, 613, (2001)) A mixtureof ethyl-1-hydroxy-3-napthylcarboxylate 46.1 (3.0 g, 13.8 mmol) and 20%Pd(OH)₂/C (1.0 g, wet) in 200 mL of MeOH is stirred under a 1 atm of H₂until TLC confirms the consumption of the starting material. Thecatalyst is filtered through celite, and the filtrate is concentrated invacuo. The residue is purified by column chromatography (silica,EtOAc/Hexane), to afford 2-napthalenecarboxylic acid,5,6,7,8-terahydro-4-hydroxy-ethyl ester 46.2.

Ethyl4-(trifluoromethylsulfonyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylate(46.3). The Triflate is formed according to the method of Kasibhatla etal. (J. Med. Chem., 44, 613, (2001)). A solution of2-napthalenecarboxylic acid, 5,6,7,8-tetrahydro-4-hydroxy-ethyl ester46.2 (2.5 g, 11.3 mmol) in 40 mL of pyridine is cooled to 0° C. andslowly treated with trifluoromethanesulfonic anhydride (2.1 mL, 12.5mmol). On warming to room temperature, the mixture is further stirreduntil TLC confirms the consumption of the starting material. The solventis evaporated, and the residue is diluted with 100 mL of water andextracted with ether. The combined organic layers are dried (MgSO₄) andconcentrated under reduced pressure to yield the title compound

Ethyl 4-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylate (46.4). Theester is formed according to the method of Molander et al. (J. Org.Chem. 68, 5534, (2003)). To a stirring suspension of potassiummethyltrifluoroborate (629.0 mg, 5.2 mmol) Cs₂CO₃ (5.0 g, 15.5 mmol),PdCl₂(dppf).CH₂Cl₂ (46.0 mg, 0.057 mmol), and triflate (46.3) (2.0 g,5.7 mmol) in 50 mL THF is added water (5 mL) under an argon atmosphere.Stirring the mixture at reflux until TLC confirms the consumption of thestarting material. The mixture is cooled to room temperature, and isdiluted with water and extracted with ether. The combined organic layersare dried (MgSO₄) and concentrated under reduced pressure. The residueis purified by column chromatography (silica, EtOAc/Hexane), to affordester 46.4.

(4-Methyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (46.5). To astirring solution of the ester 46.4 (1.5 g, 6.9 mmol) in anhydrous THF(40 mL) is added dropwise a solution of LiAlH₄ in THF (1.0 M, 13.7 mL,13.7 mmol) at 0° C. The mixture is stirred until TLC confirms theconsumption of the starting material. The reaction is slowly quenchedwith water (10 mL) at 0° C., 1N NaOH aqueous solution (50 mL) andanother portion of water (10 mL). The mixture is filtered and thefiltrate is extracted with EtOAc (3×100 mL), dried over MgSO₄ andconcentrated in vacuo. The residue is purified by column chromatography(silica, EtOAc/Hexane), to afford alcohol 46.5.

7-(Chloromethyl)-5-methyl-1,2,3,4-tetrahydronaphthalene (46.6). Alcohol46.5 (1.0 g, 5.7 mmol) is dissolved in anhydrous DCM (50 mL). Thionylchloride (619 μL, 8.5 mmol) is slowly added dropwise to the solution.The resulting mixture is stirred until TLC confirms consumption of thestarting material. The organic solvent is removed in vacuo. The residueis purified by column chromatography (silica, EtOAc/Hexane), to affordchloride 46.6.

(S)-Methyl3-(4-methyl-4H-1,2,4-triazol-3-yl)-3-(4-((4-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoate(46.7). To a stirred solution of 46.6 (100 mg, 0.38 mmol) in DMF (5 mL)at 23° C. is added resolved 13.9 (89.4 mg, 0.46 mmol) (13.9 is resolvedusing chiral chromatography as known to those skilled in the art)followed by Cs₂CO₃ (150 mg, 4.6 mmol). The resulting mixture is stirreduntil TLC confirms the consumption of the starting material. Thereaction is then diluted with EtOAc (30 mL), washed with water andbrine, dried over MgSO₄ and concentrated in vacuo. The residue ispurified by column chromatography (silica, EtOAc/Hexane), to affordester 46.7.

(S)-3-(4-Methyl-4H-1,2,4-triazol-3-yl)-3-(4-((4-methyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (46). To a stirred solution of 46.7 (150 mg, 3.6 mmol) in THF/EtOH(6 mL, 3/1, v/v) was added 1N LiOH (aq) (2 mL). The reaction mixture isstirred at 23° C. until TLC confirms consumption of the startingmaterial. The organic solvent is removed in vacuo. 1N HCl is added toneutralize the mixture to pH 7. The mixture is extracted with EtOAc(2×10 mL), concentrated in vacuo. The residue is purified by columnchromatography (silica, MeOH/DCM), to afford acid 46.

6.61 Example 47

Ethyl1-bromo-4-(trifluoromethylsulfonyloxy)-5,6,7,8-tetrahydronaphthalene-2-carboxylate(47.2). The triflate is formed according to the method of Kasibhatla etal. (J. Med. Chem., 44, 613, (2001)). A solution of alcohol 47.1 (2.5 g,8.4 mmol) in 40 mL of pyridine is cooled to 0° C. and slowly treatedwith trifluoromethanesulfonic anhydride (1.70 mL, 10.0 mmol). On warmingto room temperature, the mixture is further stirred until TLC confirmsconsumption of the starting material. The solvent is evaporated, and theresidue is diluted with 50 mL of water and extracted with ether. Thecombined organic layers are dried (MgSO₄) and concentrated under reducedpressure to yield the title compound 47.2.

1-Bromo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (47.3). The bromideis formed according to the method of Kasibhatla et al. (J. Med. Chem.,44, 613, (2001)). A solution of triflate 47.2 (2.2 g, 5.1 mmol) in 40 mLof DMF under nitrogen is stirred and tetrakis(triphenylphosphone)palladium (294 mg, 0.26 mmol) and tributyltin hydride (1.65 mL, 6.1mmol) are added. The mixture is stirred until TLC confirms consumptionof the starting material. After cooling to room temperature, the mixtureis diluted with EtOAc (30 mL), washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue is purified by columnchromatography (silica, EtOAc/Hexane), to afford ester 47.3.

(1-Bromo-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (47.4). The alcohol47.4 is formed according to the method of Basabe et al. (Tetrahedron,46, 9173, (2003)). To a stirring solution of the ester 47.3 (1.5 g, 5.3mmol) in dry DCM (40 mL) at −78° C., is added dropwise a solution ofDIBALH in toluene (1.5 M, 7.1 mL, 10.6 mmol). The mixture is stirreduntil TLC confirms consumption of the starting material. The reaction isslowly quenched with a solution of Na/K tartrate (10 mL). The mixture isfurther stirred for 2 hours. The aqueous layer is extracted with EtOAc(3×50 mL), dried over MgSO₄ and concentrated in vacuo. The residue ispurified by column chromatography (silica, EtOAc/Hexane), to affordalcohol 47.4.

2-((1-Bromo-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)-tetrahydro-2H-pyran(47.5). To a stirring solution of alcohol 47.4 (1.0 g, 4.1 mmol) in DCMat 23° C., is added 3,4-dihydro-2H-pyran (757 μL, 8.3 mmol) followed byPPTS (catalytic). The mixture is stirred until TLC confirms consumptionof the starting material. The mixture is concentrated in vacuo. Theresidue is purified by column chromatography (silica, EtOAc/Hexane), toafford the THP protected alcohol 47.5.

2-((1-Fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)-tetrahydro-2H-pyran(47.6). To stirring solution of bromide 47.5 (1.0 g, 3.1 mmol) in THF at−78° C. is added n-BuLi (1.6 M, 2.11 mL, 3.4 mmol), and stirring iscontinued for 1 hour. N-Fluorobenzene sulfonimide (3.7 mmol) is addedand the mixture is allowed to warm to 23° C. Water is added to quenchthe reaction. The aqueous layer is extracted with EtOAc (3×100 mL), andthe organic layer is dried over MgSO₄ and concentrated in vacuo. Theresidue is purified by column chromatography (silica, EtOAc/Hexane), toafford fluoride 47.6.

(1-Fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methanol (47.7). To astirring solution of 47.6 (0.75 g, 2.8 mmol) in EtOH (25 mL) at 23° C.,is added PPTS (catalytic). The mixture is stirred until TLC confirmsconsumption of the starting material. The mixture is concentrated invacuo. The residue is purified by column chromatography (silica,EtOAc/Hexane), to afford alcohol 47.7.

6-(Chloromethyl)-5-fluoro-1,2,3,4-tetrahydronaphthalene (47.8). Thealcohol 47.7 (0.5 g, 2.77 mmol) is dissolved in anhydrous DCM (50 mL).Thionyl chloride (302 μL, 4.2 mmol) is slowly added dropwise to theabove solution. The resulting mixture is stirred until TLC confirms theconsumption of the starting material. The organic solvent is removed invacuo. The residue is purified by column chromatography (silica,EtOAc/Hexane), to afford chloride 47.8.

(S)-Methyl3-(4-((1-fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)propanoate(47.9). To a stirred solution of resolved 13.9 (0.1 g, 0.38 mmol) (13.9is resolved using chiral chromatography ask known to those skilled inthe art) in DMF (5 mL) at 23° C., is added 47.8 (91.2 mg, 0.46 mmol)followed by Cs₂CO₃ (150 mg, 0.46 mmol). The resulting mixture is stirreduntil TLC confirms consumption of the starting material. The reaction isthen diluted with EtOAc (30 mL), washed with water and brine, dried overMgSO₄ and concentrated in vacuo. The residue is purified by columnchromatography (silica, EtOAc/Hexane), to afford ester 47.9.

(S)-3-(4-((1-Fluoro-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)propanoicacid (47). To a stirred solution of 47.9 (100 mg, 0.24 mmol) in THF/EtOH(6 mL, 3/1, v/v) is added 1N LiOH (aq) (2 mL). The reaction mixture isstirred at 23° C. until TLC confirms consumption of the startingmaterial. The organic solvent is removed in vacuo. 1N HCl is added toneutralize the mixture to pH 7. The mixture is extracted with EtOAc(2×10 mL), concentrated in vacuo. The residue is purified by columnchromatography (silica, MeOH/DCM), to afford acid 47.

6.62 Example 48

Synthesis of Compound 48. Compound 48 is synthesized using the procedurefor preparing Example 6 using compound M5. Separation of the enantiomersof starting material M5 is accomplished using the procedure describedherein and reacted with the benzyl bromide to provide the R and Senantiomers of 48. Alternatively, a racemic mixture of 48 can beseparated on a chiral column to afford the individual enantiomers.

6.63 Example 49

Synthesis of Compound 51. Compound 49 is synthesized using the procedurefor preparing Example 6 using compound M10. Separation of theenantiomers of starting material M10 is accomplished using the proceduredescribed herein and reacted with the benzyl bromide to provide the Rand S enantiomers of 49. Alternatively, a racemic mixture of 49 can beseparated on a chiral column to afford the individual enantiomers.

6.64 Example 50

Synthesis of Compound 50. Compound 50 is synthesized using the procedurefor preparing Example 6 using compound M6. Separation of the enantiomersof starting material M6 is accomplished using the procedure describedherein and reacted with the benzyl bromide to provide the R and Senantiomers of 50. Alternatively, a racemic mixture of 50 can beseparated on a chiral column to afford the individual enantiomers.

6.65 Example 51

Synthesis of Compound 51. Compound 51 is synthesized using the procedurefor preparing Example 6 using compound M7. Separation of the enantiomersof starting material M7 is accomplished using the procedure describedherein and reacted with the benzyl bromide to provide the R and Senantiomers of 51. Alternatively, a racemic mixture of 51 can beseparated on a chiral column to afford the individual enantiomers.

6.66 Example 52

Synthesis of Compound 52. Compound 52 is synthesized using the procedurefor preparing Example 6 using compound M8. Separation of the enantiomersof starting material M8 is accomplished using the procedure describedherein and reacted with the benzyl bromide to provide the R and Senantiomers of 52. Alternatively, a racemic mixture of 52 can beseparated on a chiral column to afford the individual enantiomers.

6.67 Example 53

Synthesis of Compound 53. Compound 53 is synthesized using the procedurefor preparing Example 6 using compound M9. Separation of the enantiomersof starting material M9 is accomplished using the procedure describedherein and reacted with the benzyl bromide to provide the R and Senantiomers of 53. Alternatively, a racemic mixture of 53 can beseparated on a chiral column to afford the individual enantiomers.

6.68 Example 54

(S)-Ethyl3-(4-((8,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(54.1). To a solution of(8,8-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)methanol (191 mg, 1 mmol;prepared according to D. Guay et al, Bioorg. Med. Chem. Lett. 1998, 8,453-458), triphenylphosphine (288 mg, 1.1 mmol) and compound M12 (274mg, 1 mmol) in THF (0.5 mL), is added slowly diethyl azodicarboxylate(174 mg, 1 mmol) at room temperature. The reaction mixture is stirred atroom temperature for 30 minutes before loading on a silica gel cartridgeand chromatographing (silica gel, 1:4 EtOAc/hexane) to afford compound54.1.

(S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (54). 10% NaOH (aq) (1 mL) is added to a solution of compound 54.1(45 mg, 0.1 mmol) in EtOH (2 mL). The reaction mixture is stirred atroom temperature for 4 hours. 1N HCl is added to neutralize the mixtureto pH 6-7. The mixture is extracted with EtOAc (2×20 mL), washed withwater and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue is flash chromatographed (silica gel,0-10% MeOH in DCM) to afford the compound 54.

6.69 Examples 55 and 56

(S)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methoxy)phenyl)propanoate(55). To a solution of(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methanol (220 mg,1 mmol; prepared according to K. Kikuchi et al, J. Med. Chem. 2000, 43,409-419), triphenylphosphine (288 mg, 1.1 mmol) and compound M12 (274mg, 1 mmol) in THF (0.5 mL), is added slowly diethyl azodicarboxylate(174 mg, 1 mmol) at room temperature. The reaction mixture is stirred atroom temperature for 30 minutes before loading on a silica gel cartridgeand chromatographing (silica gel, 1:4 EtOAc/hexane) to afford thecompound 55.

(S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methoxy)phenyl)propanoicacid (56). 10% NaOH_((aq)) (1 mL) is added to a solution of compound 55(47 mg, 0.1 mmol) in EtOH (2 mL). The reaction mixture is stirred atroom temperature for 4 hours. 1N HCl is added to neutralize the mixtureto pH 6-7. The mixture is extracted with EtOAc (2×20 mL), washed withwater and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue is flash chromatographed (silica gel,0-10% MeOH in DCM) to afford compound 56.

6.70 Example 57

(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanethiol(57.1). 6-Bromomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene57.1 (available from Maybridge) is converted directly to the compound57.2 by the published method of Yoon (Synthesis 1995, 373-75).

(+/−)-3-(4-((5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methylthio)phenyl)hex-4-ynoicacid (57). Thiol 57.2 is converted to the title compound 57 according bya method analogous to that disclosed in Example 28 set forth in US2006/0004012 which is hereby incorporated by reference.

6.71 Example 58

5-Bromo-3,3-dimethyl-2,3-dihydrobenzofuran (58.3). Compound 58.3 issynthesized using a literature procedure (J. Med. Chem. 1987, 30,1474-1482).

1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)ethanone (58.4). Compound58.4 is synthesized using a literature procedure (J. Med. Chem. 1998,41, 3753-3757).

3,3-Dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (58.5). Compound58.5 is synthesized using a literature procedure (J. Med. Chem. 1997,40, 3567-3583).

(3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)methanol (58.6). Compound 58.6is prepared using the procedure of Example 2.2 set forth in US2006/0004012 which is hereby incorporated by reference.

5-(Bromomethyl)-3,3-dimethyl-2,3-dihydrobenzofuran (58.7). Compound 58.7is prepared using the procedure of Example 2.3 set forth in US2006/0004012 which is hereby incorporated by reference.

(S)-3-(4-((3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (58). Compound 58 is obtained from compound 58.7 and M12 (seeMethod 12) using the general procedure A.

6.72 Example 59

1-(4,4-Dimethylchroman-6-yl)ethanone (59.1). Compound 59.1 issynthesized using a literature procedure (J. Med. Chem. 1985, 28,116-124).

4,4-Dimethylchroman-6-carboxylic acid (59.2). Compound 59.2 issynthesized using a literature procedure (J. Med. Chem. 1997, 40,3567-3583).

(4,4-Dimethylchroman-6-yl)methanol (59.3). Compound 59.3 is preparedusing the procedure of Example 2.2 set forth in US 2006/0004012 which ishereby incorporated by reference.

6-(Bromomethyl)-4,4-dimethylchroman (59.4). Compound 59.4 is preparedusing the procedure of Example 2.3 set forth in US 2006/0004012 which ishereby incorporated by reference.

(S)-3-(4-((4,4-dimethylchroman-6-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoicacid (59). Compound 59 is obtained from compound 59.4 and 59.5 (methylester 59.5 is prepared using the same procedure used to prepare ethylester 6.6 using methanol instead of ethanol) (see Example 6) using theprocedure of Example 6.

6.73 Example 60

Benzyl Alcohol (60.4). Compound 60.4 is obtained using methods known tothose skilled in the art (JACS 1972, 94(9), 3143-3148). Compound 60.1 isreduced with SnCl₂ to provide the corresponding aniline. The aniline istransformed to the aryl iodide 60.2 by treating with NaNO₂ and HCl inthe presence of KI. The iodide 60.2 is converted to the correspondingacid 60.3 by lithium halogen exchange with s-BuLi followed by trappingwith DMF. The acid 60.3 is reduced with borane to provide the benzylalcohol 60.4.

(S)-3-(4-((2-Benzylisoindolin-5-yl)methoxy)phenyl)hex-4-ynoic acid (60).Compound 60.4 and M1 are reacted under Mitsunobu conditions and theresulting ester 60.5 is hydrolyzed by a method analogous to thatdisclosed in Example 16 to provide 60.

6.74 Example 61

(2-Benzylisoindolin-5-yl)methanol (61.2). 61.1 is prepared according tothe published method of Miyachi (Bioorganic & Medicinal ChemistryLetters 2005, 15, 4427-4431). To a stirred 20 mL THF solution of AM.1(2.67 g, 10 mmol), is added dropwise IN LiAlH₄ 30 mL over 30 minutes at0° C. under N₂. After completion, the solution is heated at reflux for 2hours. The solution is cooled to room temperature, quenched withsaturated NH₄Cl, extracted with DCM, dried over MgSO₄, concentratedunder reduced pressure, and the residue purified by flash chromatographywith EtOAc and hexanes as the mobile phase to obtain 61.2.

(S)-3-(4-((2-benzylisoindolin-5-yl)methoxy)phenyl)hex-4-ynoic acid (61).Compound 61.2 and M1 are reacted under Mitsunobu conditions and theresulting ester hydrolyzed by a method analogous to that disclosed inExample 16.

6.75 Example 62 Synthesis of(S)-3-(4-((3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (62)

6-Bromo-7-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene(62.2). The mixture of6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g,1.8 mmol) and CCl₄ (120 mL) was heated at reflux for 16 hours. Themixture was concentrated under reduced pressure to about 50 mL. Thereaction was then filtered, and the solid was washed with Et₂O (20 mL).The combined organic solution was then concentrated under vacuum togenerate crude product. Crude 62.2 was generated as a brown oil and useddirectly in the next step without further purification.

(S)-3-(4-((3-Bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (62). Compound 62.3 was obtained from compound M12 and 62.2following the general procedure E and isolated as a generalintermediate. Compound 62 was obtained from compound 62.3 by followingthe general procedure E. LC-MS ESI (neg.) M/E: 523 (M−H). ¹HNMR (500MHz, MeOH-d₄, ppm) δ 7.52 (s, 1H), 7.43 (s, 1H), 7.18-7.21 (m, 4H),6.96-7.20 (m, 2H), 5.07 (s, 2H), 4.73 (dd, 1H J=5 Hz, 10 Hz), 3.65 (s,3H), 3.27 (dd, 1H, J=5 Hz, 10 Hz), 2.98 (dd, 1H, J=5 Hz, 10 Hz), 1.70(s, 4H), 1.28 (s, 6H), 1.22 (s, 6H).

6.76 Example 63 Synthesis of(S)-3-(4-((3-cyclopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (63)

(S)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoate(63.1). The mixture of compound 62 (166 mg, 0.3 mmol), cyclopropylboronic acid (129 mg, 1.5 mmol), K₃PO₄ (212 mg, 1 mmol), Pd(OAc)₂ (26mg, 0.12 mmol), Sphos (100 mg, 0.24 mmol) and dioxane (3 mL) was purgedwith nitrogen, and then heated at 100° C. overnight. The reactionmixture was directly purified by CombiFlash. The compound 63.1 wasgenerated as a colorless oil. LC-MS ESI (pos.) M/E: 515 (M+H).

(S)-3-(4-((3-Cyclopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (63). Compound 63 was obtained from compound 63.1 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 485 (M−H). ¹HNMR (500 MHz,MeOH-d₄, ppm) δ 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.23-7.25 (m,2H), 7.05-7.07 (m, 2H), 7.01 (s, 1H), 5.22 (s, 2H), 4.97 (dd, 1H J=5 Hz,10 Hz), 3.85 (s, 3H), 3.26 (dd, 1H, J=10 Hz, 15 Hz), 3.19 (dd, 1H, J=10Hz, 20 Hz), 1.96 (m, 1H), 1.69 (s, 4H), 1.26 (s, 6H), 1.23 (s, 6H),0.87-0.90 (m, 2H), 0.62-0.65 (m, 2H).

6.77 Example 64 Synthesis of(S)-3-(4-((3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (64)

(S)-3-(4-((3-Methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (64). Compound 64 was obtained from compound 62 and methyl boronicacid by following the same procedure used for compound 63. LC-MS ESI(neg.) M/E: 459 (M−H). ¹HNMR (500 MHz, MeOH-d₄, ppm) δ 7.53 (s, 1H),7.51 (s, 1H), 7.27 (s, 1H), 7.22-7.24 (m, 2H), 7.15 (s, 1H), 7.04-7.07(m, 2H), 5.03 (s, 2H), 4.97 (dd, 1H J=5 Hz, 10 Hz), 3.85 (s, 3H), 3.36(dd, 1H, J=10 Hz, 20 Hz), 3.19 (dd, 1H, J=10 Hz, 20 Hz), 2.30 (s, 3H),1.70 (s, 4H), 1.28 (s, 6H), 1.24 (s, 6H).

6.78 Example 65 Synthesis of(S)-3-(4-((3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (65)

(S)-3-(4-((3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (65). Compound 65 was obtained from compound 65 and ethyl boronicacid by following the same procedure as used for compound 63. LC-MS ESI(neg.) M/E: 473 (M−H). ¹HNMR (500 MHz, MeOH-d₄, ppm) δ 7.53 (s, 1H),7.51 (s, 1H), 7.29 (s, 1H), 7.22-7.26 (m, 2H), 7.19 (s, 1H), 7.03-7.07(m, 2H), 5.05 (s, 2H), 4.97 (dd, 1H J=5 Hz, 10 Hz), 3.86 (s, 3H), 3.36(dd, 1H, J=10 Hz, 15 Hz), 3.20 (dd, 1H, J=10 Hz, 20 Hz), 2.66 (q, 2H,J=10 Hz), 1.71 (s, 4H), 1.29 (s, 6H), 1.25 (s, 6H), 1.22 (t, 3H, J=10Hz).

6.79 Example 66 Synthesis of(R/S)-3-(1-methyl-1H-imidazol-2-yl)-3-[4-(4,4,7,7-tetramethyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-ylmethoxy)-phenyl]-propionicacid (66)

(R/S)-3-(1-Methyl-1H-imidazol-2-yl)-3-[4-(4,4,7,7-tetramethyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-ylmethoxy)-phenyl]-propionicacid (66). Compound 66.3 is obtained by the reaction of2-methylthiophene 66.2 with 2,5-dichloro-2,5-dimethyl-hexane 66.1according to the procedure of Faul et al, JOC, 66, 5772 (2000) or WO96/13478. Compound 66.4 is obtained by the reaction of 66.3 with NBS andAIBN. Compound 66 is obtained from compound M12 and 66.4 using thecoupling and saponification procedures described herein.

6.80 Example 67 Synthesis of Compound 67

Compound 67. Compound 67 is obtained from reaction of compound M12 and67.1 using the coupling and saponification procedures described herein.

6.81 Example 68 Synthesis of Compound 68

Compound 68. Compound 68 is obtained from reaction of compound M12 and68.1 using the coupling and saponification procedures described herein.

6.82 Example 69 Synthesis of Compound 69

Compound 69. Compound 69 is obtained from reaction of compound M12 and69.1 using the coupling and saponification procedures described herein.

6.83 Example 70 Synthesis of Compound 70

Compound 70. Compound 70 is obtained from reaction of compound M12 and70.1 using the coupling and saponification procedures described herein.

6.84 Example 71 Synthesis of Compound 71

Compound 71. Compound 71 is obtained from reaction of compound M12 and71.1 using the coupling and saponification procedures described herein.

6.85 Example 72 Synthesis of(S)-3-(4-((8,8-diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(isoxazol-3-yl)propanoicacid (72)

Starting from 18.2 and 59.5 (methyl ester was prepared using the sameprocedure used to prepare ethyl ester 6.6 using methanol instead ofethanol), compound 72 was prepared using a procedure analogous to thatdescribed in Example 16. MS ESI (pos.) m/e: 462.1 (M+H). ¹H NMR(MeOH-d₄) δ 8.50 (s, 1H), 7.34 (d, 1H, J=8.07 Hz), 7.21-7.15 (m, 4H),6.94 (d, 2H, J=8.80 Hz), 6.28 (d, 1H, J=1.71 Hz), 5.02 (s, 2H), 4.57 (t,1H, J=7.82 Hz), 3.20 (dd, 1H, J1=8.07 Hz, J2=8.07 Hz), 2.94 (dd, 1H,J1=7.33 Hz, J2=8.80 Hz), 1.73 (m, 6H), 1.55 (m, 2H), 1.27 (s, 6H), 0.72(t, 6H, J=7.58 Hz).

5.86 Example 73 Synthesis of(S)-3-(4-((8,8-diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-tetrazol-5-yl)propanoicacid (73)

Starting from 18.2 and M14, compound 73 was prepared using a procedureanalogous to that described in Example 16. MS ESI (pos.) m/e: 477.2(M+H). ¹H NMR (MeOH-d₄) δ 7.35 (d, 1H, J=8.07 Hz), 7.21-7.19 (m, 3H),7.16 (dd, 1H, J1=1.71 Hz, J2=8.07 Hz), 6.97 (d, 2H, J=8.80 Hz), 5.04 (s,2H), 4.74 (dd, 1H, J1=5.62 Hz, J2=9.78 Hz), 3.91 (s, 3H), 3.42 (m, 1H),3.03 (m, 1H), 1.71 (m, 6H), 1.54 (m, 2H), 1.27 (s, 6H), 0.70 (t, 6H,J=5.13 Hz).

6.86 Example 74 Synthesis of3-(4,5-dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid

(S)-4-Benzyl-3-((S)-3-(4-(benzyloxy)phenyl)-3-(4,5-dihydroisoxazol-3-yl)propanoyl)oxazolidin-2-one(74.1). Ethylene was bubbled into 72.3 (882 mg, 1.86 mmol) in 40 mL ACNat room temperature for 20 minutes. (Boc)₂O (610 mg, 2.79 mmol) wasadded at room temperature, followed by the addition of DMAP (23 mg, 0.19mmol). The mixture was stirred at room temperature for 6 hours. AfterHPLC indicated that all the 72.3 was consumed, the reaction mixture wastaken into EtOAc (500 mL) and saturated sodium bicarbonate (400 mL). Theorganic layer was separated, washed with brine, dried, and concentratedunder vacuum. The crude product was purified by flash chromatography togive 74.1 800 mg). MS ESI (pos.) m/e: 485 (M+H).

(S)-4-Benzyl-3-((S)-3-(4-hydroxyphenyl)-3-(4,5-dihydroisoxazol-3-yl)propanoyl)oxazolidin-2-one (74.2). Compound 74.1 (136 mg) and acatalytic amount of Pd/C in EtOH (2 mL) was stirred at room temperatureunder 1 atm of H₂ for 2.5 hours. The catalyst was removed by filtration,and the filtrate was concentrated to give 74.2 (100 mg). MS ESI (pos.)m/e: 395 (M+H).

3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (74). Compound 74 was synthesized using the procedure above forpreparing compound 15. MS ESI (pos.) m/e: 436 (M+H). ¹HNMR (CDCl₃) δ7.35 (m, 2H), 7.19 (m, 3H), 6.96 (d, 2H), 4.97 (s, 2H), 4.28 (m, 2H),4.07 (t, 1H), 3.28 (dd, 1H), 2.79 (m, 3H), 1.71 (s, 4H), 1.30 (s, 12H).

5.86 Example 75 Synthesis of(S)-3-(4-((5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (75)

Starting from 75.1 and M12, compound 75 was prepared using a procedureanalogous to that described in Example 16. Material 75.1 was preparedaccording to the similar published procedure of Endo, Y. et al. (J. Med.Chem. 1998, 41, 1476-1496). MS ESI (pos.) m/e: 419.2 (M+H). ¹H NMR(MeOH-d₄) δ 7.51 (dd, 2H, J1=1.95 Hz, J2=11.9 Hz), 7.34 (d, 1H, J=8.06Hz), 7.22 (m, 2H), 7.16 (d, 1H, J=8.32 Hz), 7.07 (s, 1H), 7.03 (m, 2H),5.01 (s, 2H), 4.95 (m, 1H), 3.85 (s, 3H), 3.37 (m, 1H), 3.21 (m, 1H),2.76 (t, 2H, J=6.35 Hz), 1.82 (m, 2H), 1.70 (m, 2H), 1.29 (s, 6H).

5.86 Example 76 Synthesis of Compound 76

Compound 76.1. To a flask containing ethyl 3-methyl-4-nitrobenzoate(3.56 g, 17.0 mmol)(commercially available from Alfa Aesar),4-chlorobenzaldehyde (2.0 g, 14.2 mmol), and 1M Bu₄NF in THF (25.6 mL,25.6 mmol), was added NEt(i-Pr)₂ (5.6 mL, 34.1 mmol). The mixture washeated to reflux overnight. The reaction was concentrated in vacuo andthe residue was purified by flash chromatography (SiO₂ gel 60, elutedwith 0 to 20% EtOAc in hexanes). Fractions containing the desiredproduct were combined and concentrated to provide a yellow solid (1.093g, 25%). The enantiomers were resolved by chiral HPLC (Chiralcel OD-Hcolumn, 10% IPA/hexane, 220 nm) to afford 76.1 (0.525 g, 12.0% yield,8.33 minutes) and 76.2 (0.520 g, 12.0% yield, 16.1 minutes). Theabsolute configurations were assigned arbitrarily. ¹H NMR spectroscopyanalysis was consistent with the desired products.

Compound 76.3. A flask containing 76.1 (0.800 g, 2.64 mmol) in THF (40mL) was cooled to −78° C. and DIBALH was then slowly added. The reactionwas stirred at −78° C. for one hour and then allowed to warm to roomtemperature. The reaction was carefully quenched with an aqueoussaturated solution of Rochelle's salt and then extracted with EtOAc,dried over sodium sulfate, filtered, and concentrated to provide 76.3(0.79 g, 3.03 mmol, 92% yield).

Compound 76.4. To M1 (50 mg, 0.23 mmol), 76.3 (60 mg 0.23 mmol), andtriphenylphosphine (60 mg, 0.23 mmol) in THF was added DEAD (46 μL, 0.25mmol). The resulting reaction mixture was then stirred overnight. Thereaction was concentrated and purified by flash chromatography (SiO₂ gel60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing thedesired product were combined and concentrated to provide 76.4 (30 mg,28% yield).

(S)-3-(4-(((S)-2-(4-Chlorophenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)hex-4-ynoicacid (76). Compound 76 was synthesized using the procedure above forpreparing Example 6 using compound 76.4. ¹HNMR (CDCl₃) δ 7.35-7.20 (8H,m), 6.94 (2H, d, J=8.6 Hz), 6.87 (1H, d, J=8.3 Hz), 5.76 (1H, m), 4.96(2H, s), 3.65 (1H, dd, J=9.5, 15.7 Hz), 3.18 (1H, dd, J=8.1, 15.9 Hz),2.82 (1H, dd, J=8.6, 15.9 Hz), 2.73 (1H, dd, J=6.6, 15.9 Hz), 1.85 (3H,d, J=2.0 Hz).

5.87 Examples 77 Synthesis of Compound 77

Compound 77.1. A flask containing 76.2 (0.800 g, 2.64 mmol) in THF (40mL) was cooled to −78° C. and then DIBALH was added slowly. The reactionwas stirred at −78° C. for one hour and then warmed to room temperature.The reaction was carefully quenched with an aqueous saturated solutionof Rochelle's salt and then extracted with EtOAc, dried over sodiumsulfate, filtered, and concentrated to provide 76.3 (0.79 g, 3.03 mmol,92% yield).

Compound 77.2. To M1 (50 mg, 0.23 mmol), 77.1 (60 mg 0.23 mmol), andtriphenylphosphine (60 mg, 0.23 mmol) in THF was added DEAD (46 μL, 0.25mmol) and allowed to stir overnight. The reaction was concentrated andpurified by flash chromatography (SiO₂ gel 60, eluted with 0 to 20%EtOAc in hexanes). Fractions containing the desired product werecombined and concentrated to provide 77.2 (30 mg, 28% yield).

(S)-3-(4-(((R)-2-(4-Chlorophenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)hex-4-ynoicacid (77). Compound 77 was synthesized using the procedure above forpreparing Example 6 using compound 77.2. ¹HNMR (CDCl₃) δ 7.35-7.20 (8H,m), 6.94 (2H, d, J=8.6 Hz), 6.87 (1H, d, J=8.3 Hz), 5.76 (1H, m), 4.96(2H, s), 3.65 (1H, dd, J=9.5, 15.7 Hz), 3.18 (1H, dd, J=8.1, 15.9 Hz),2.82 (1H, dd, J=8.6, 15.9 Hz), 2.73 (1H, dd, J=6.6, 15.9 Hz), 1.85 (3H,d, J=2.0 Hz).

5.86 Examples 78 Synthesis of Compound 78

Compound 78.1. To stirred solution of phenol M1 (2.0 g, 9.2 mmol, 1 eq.,MW 218.25) in DCM at 23° C. was added 3,4-dihydro-2H-pyran (1.7 mL, 18.4mmol, 2 eq., MW 84.12) followed by PPTS (catalytic, MW 251.31). Theresulting mixture was stirred for 16 hours and concentrated in vacuo.The residue was then purified by flash chromatography (SiO₂ gel 60,eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desiredproduct were combined and concentrated to provide 78.1 as a colorlessoil (2.6 g, 94%). MS ESI (pos.) m/e: 325.1 (M+Na)⁺, 320.2 (M+H₂O)⁺.

Compound 78.2. To a stirred solution of 78.1 (1.00 g, 3.3 mmol, MW302.37) in THF at 23° C. was added PdCl₂(PPh₃)₂ (232.0 mg, 0.30 mmol, MW701.89) followed by Bu₃SnH (964.0 μL, 3.6 mmol, MW 291.05). After theaddition, the solution turned black. After a further 2 minutes, themixture was concentrated in vacuo. The residue was then purified byflash chromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc inhexanes). Fractions containing the desired product were combined andconcentrated to provide a colorless oil (760.0 mg, 39%). ¹H NMRspectroscopy analysis was consistent with the desired product.

Compound 78.3. To a stirred solution of 78.2 (760.0 mg, 1.2 mmol, 1 eq.,MW 593.42) in THF (45 mL) at −78° C., was added iodine (357.0 mg, 1.4mmol, 1.1 eq., MW 253.81) in THF (5 mL) dropwise. After the addition wascomplete, a saturated solution of NaS₂O₃ and NaHCO₃ were added at thesame time to quench the reaction. EtOAc was added to the mixture, andthe resulting mixture was washed with NaHCO₃ (aq) (2×100 mL) and brine(1×100 mL). The organic layer was dried over MgSO₄ and filtered. Theorganic layer was concentrated in vacuo. The residue was then purifiedby flash chromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc inhexanes). Fractions containing the desired product were combined andconcentrated to provide 78.3 as a colorless oil (440 mg, 80%). MS ESI(pos.) m/e: 453.0 (M+Na)⁺, 448.1 (M+H₂O)⁺.

Compound 78.4. To a stirred solution of 78.3 (440.0 mg, 1.02 mmol, 1eq., MW 430.29) in THF (30 mL) at 0° C., was added Pd(PPh₃)₄ (118 mg,0.10 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of Et₂Zn(1.22 mL, 1.22 mmol, 1.2 eq., 1.0 M). The reaction was warmed to roomtemperature. After 30 minutes, TLC showed that the reaction wascomplete. Water (10 mL) was added to quench the reaction. The mixturewas extracted with EtOAc (2×50 mL), dried with MgSO₄, and filtered. Theorganic layer was concentrated in vacuo. The residue was then purifiedby flash chromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc inhexanes). Fractions containing the desired product were combined andconcentrated to provide 78.4 as a colorless oil (320 mg, 94%).

Compound 78.5. To a stirred solution of 78.4 (320.0 mg, 0.96 mmol, MW332.44) in EtOH (10 mL) at 23 C, was added PPTS (catalytic). Stirringwas continued for 12 hours. The reaction was concentrated in vacuo. Theresidue was then purified by flash chromatography (SiO₂ gel 60, elutedwith 0 to 20% EtOAc in hexanes). Fractions containing the desiredproduct were combined and concentrated to provide a colorless oil. Thedesired product was contaminated (˜5%) with a further olefinic product.This impurity was removed by further purification on silica gelcontaining 10% AgNO₃ eluting with 0 to 20% EtOAc in hexanes. Thecombined fractions were concentrated under reduced pressure to affordphenol 78.5 (203 mg, 85%) as a colorless oil.

(R,E)-5-Methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hept-4-enoicacid (78). Compound 78 was synthesized using the procedure above forpreparing Example 6 using compound 78.5. MS ESI (neg.) m/e: 867 (2M−H),433 (M−H). ¹HNMR (CDCl₃) δ 7.35-7.33 (2H, m), 7.23-7.17 (3H, m), 6.94(2H, d, J=8.2 Hz), 5.27 (1H, dd, J=9.4, 1.2 Hz), 4.97 (2H, s), 4.04 (1H,m), 2.77-2.71 (1H, dd, J=15.0, 7.1 Hz), 2.65-2.59 (1H, dd, J=8.2, 15.0Hz), 2.00 (2H, q, J=7.3 Hz), 1.71-1.69 (7H, m), 1.30 (12H, s), 0.98 (3H,t, J=7.3 Hz).

Compound 79.1. By changing the resolving agent used in Example 19 to(1R,2S)-1-amino-2-indanol, compound 20.1 was obtained by the procedureof Example 1 set forth in US 2006/0004012 which is hereby incorporatedby reference. Compound 79.1 was synthesized using the procedure abovefor preparing Example 78 using compound 20.1.

(S,E)-5-Methyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hept-4-enoicacid (79). Compound 79 was synthesized using the procedure above forpreparing Example 6 using compound 79.1. MS ESI (neg.) m/e: 867 (2M−H),433 (M−H). ¹HNMR (CDCl₃) δ 7.37-7.35 (2H, m), 7.24-7.20 (3H, m), 6.96(2H, d, J=8.2 Hz), 5.29 (1H, dd, J=9.4, 1.2 Hz), 4.98 (2H, s), 4.06 (1H,m), 2.78-2.72 (1H, dd, J=15.0, 7.1 Hz), 2.66-2.60 (1H, dd, J=8.2, 15.0Hz), 2.01 (2H, q, J=7.3 Hz), 1.72-1.70 (7H, m), 1.31 (12H, s), 1.00 (3H,t, J=7.3 Hz).

6.87 Example 80((S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-((1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)propanoicacid (80)

5-(Bromomethyl)-1,1,3,3-tetramethyl-2,3-dihydro-1H-indene (80.2)1,1,3,3,5-Pentamethylindane (80.1) can be prepared according to themethod given in U.S. Pat. No. 4,551,573. A mixture of 80.1 (100 mg, 0.53mmol), N-bromosuccinimide (NBS) (114 mg, 0.64 mmol), and dibenzoylperoxide (13 mg, 0.05 mmol) in CCl₄ (5 mL) was heated to reflux for 4hours. The reaction was cooled, and the precipitate was filtered out.The solvent was removed to afford crude 80.2, which was used directly inthe next step.

(S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-((1,1,3,3-tetramethyl-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)propanoicacid (80) Compound 80 was prepared using a procedure analogous to thatdescribed in Example 16 starting with the imidazole phenol M12 shown inthe reaction scheme and 80.2. MS ESI (pos.) m/e: 433.1 (M+H). ¹HNMR(MeOH-d₄) δ 7.52 (d, 1H, J=1.96 Hz), 7.49 (d, 1H, J=1.96 Hz), 7.24-7.11(m, 5H), 7.05-7.02 (m, 2H), 5.06 (s, 2H), 4.97-4.93 (m, 1H), 3.84 (s,3H), 3.41-3.34 (m, 1H), 3.20-3.16 (m, 1H), 1.94 (s, 2H), 1.30 (s, 12H).

6.88 Example 81(S)-3-(4-((5,5-dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (81)

7-(Bromomethyl)-4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one (81.2).Compound 81.1 can be prepared according to the method of Blaskovich(Bioorg. Med. Chem. Lett. 2003, 13, 2083-85). Intermediate 81.2 wasprepared using a procedure analogous to that described in Example 80starting with 81.1 The crude product was directly used in the next step.

(S)-3-(4-((5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (81) Compound 81 was prepared using a procedure analogous to thatdescribed in Example 16 starting with the imidazole phenol M12 shown inthe reaction scheme and 81.2. MS ESI (pos.) m/e: 433.1 (M+H). ¹HNMR(CDCl₃-d) δ 7.98 (s, 1H), 7.65-7.47 (m, 4H), 7.21 (d, 2H, J=8.80 Hz),7.03 (d, 2H, J=8.40 Hz), 5.11 (s, 2H), 4.95-4.89 (m, 1H), 3.82 (s, 3H),3.39-3.35 (m, 1H), 3.18-3.14 (m, 1H), 2.73 (s, 2H, J=6.35 Hz), 2.04 (t,2H, J=6.35 Hz), 1.40 (s, 6H).

Example 82

2,2-Difluorobenzo[d][1,3]dioxol-5-yl)methanol (82.2). Sodium borohydride(0.58 g, 15.4 mmol) was added in portions to a cold solution of 82.1(1.00 mL, 7.63 mmol) in dry MeOH (12.0 mL). The mixture was stirred at0° C. for 1 hour and then stirred at room temperature for 3 hours. Thereaction was carefully quenched with cold water and then extracted threetimes with ether. The combined organic extracts were dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue was thenpurified by flash chromatography (SiO₂ gel 60, eluted with 0 to 50%EtOAc in hexanes). Fractions containing the product 82.2 were combinedand concentrated to provide the product as a colorless oil (0.90 g,63%). ¹H NMR (500 MHz) (CDCl₃) δ 7.08 (1H, m), 7.03, (2H, m), 4.62 (2H,s), 2.51, (1H, s).

5-(Chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole (82.3). Thionylchloride (0.53 mL, 7.27 mmol) was added dropwise to a cold solution of82.2 (0.90 g, 4.79 mmol) in dry DCM (10 mL). The mixture was allowed towarm to room temperature. After 19 hours, the mixture was concentratedand then purified by flash chromatography (SiO₂ gel 60, eluted with 0 to30% EtOAc in hexanes). Fractions containing the desired product 82.3were combined and concentrated to provide the product as a colorless oil(0.90 g, 63%). ¹H NMR (500 MHz) (CDCl₃) δ 7.00 (2H, m), 6.88, (1H, d,J=8.1 Hz), 4.43 (2H, s).

(S)-Ethyl3-(4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(82.4). Compound 82.4 was prepared by a method analogous to that ofGeneral procedure A for 5.15.1. MS ESI (pos.) m/e: 445.1 (M+H)⁺.

(S)-3-(4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (82). Compound 82 was prepared by a method analogous to that ofGeneral Procedure A for 5.15.1. MS ESI (neg.) m/e: 417.1 (M−H). ¹H NMR(500 MHz) (DMSO-d₆) δ 7.48 (1H, s), 7.40 (1H, d, J=8.2 Hz), 7.28 (1H, d,J=8.2 Hz), 7.12 (2H, d, J=7.9 Hz), 6.98 (1H, s), 6.92 (2H, d, J=7.9 Hz),6.79 (1H, s), 5.04 (2H, s), 4.50 (1H, m), 3.42 (3H, m), 3.15 (1H, dd,J=16.3, 9.0 Hz), 2.73 (1H, dd, J=16.2, 5.8).

Example 83

Ethyl (3S)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-pentynoate(83.2). Compound 83.1 was prepared by a method based on that reported inBiochemistry 1989, 28, 3833-3842. To stirred solution of phenol 83.1(1.0 g, 4.6 mmol, 1 eq., MW 218.25) in DCM at 23° C. was added3,4-dihydro-2H-pyran (839 μL, 9.2 mmol, 2 eq., MW 84.12) followed byPPTS (catalytic, MW 251.31). The resulting mixture was stirred for 16hours and concentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product were combined and concentratedto a colorless oil (1.3 g, 94%). MS ESI (pos.) m/e: 325.1 (M+Na)⁺, 320.2(M+H₂O)⁺.

Ethyl(3S)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-5-(tributylstannanyl)-4-pentenoate(83.3). To a stirred solution of 83.2 (80.0 mg, 0.26 mmol, MW 302.37) inTHF at 23° C. was added PdCl₂(PPh₃)₂ (18.6 mg, 0.026 mmol, MW 701.89)followed by Bu₃SnH (84.0 μL, 0.32 mmol, MW 291.05). After the addition,the solution turned black. After a further 2 minutes, the mixture wasconcentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product 83.3 were combined andconcentrated to provide a colorless oil (96.0 mg). ¹H NMR spectroscopyshowed the product to be a 3:1 ratio of 83.3:83.3a respectively.

Ethyl(3S,4E)-5-iodo-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-pentenoate(83.4). To a stirred solution of 83.3/83.3a (96.0 mg, 0.16 mmol, 1 eq.,MW 593.42) in THF (5 mL) at −78° C. was added iodine (45.0 mg, 0.18mmol, 1.1 eq., MW 253.81) in THF (2 mL) dropwise. After the addition wascomplete, a saturated solution of NaS₂O₃ and NaHCO₃ were added at thesame time to quench the reaction. EtOAc was added to the mixture, andthe resulting mixture was washed with NaHCO₃ (aq) (2×50 mL) and brine(1×50 mL). The organic layer was dried over MgSO₄ and filtered. Theorganic layer was concentrated in vacuo. The residue was then purifiedby flash chromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc inhexanes). Fractions containing the desired product were combined andconcentrated to a colorless oil (66 mg, 58% over 2 steps). MS ESI (pos.)m/e: 453.0 (M+Na)⁺, 448.1 (M+H₂O)⁺.

(3R,E)-Ethyl6-phenyl-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)hex-4-enoate (83.5).To a stirred solution of 83.4 (571.9 mg, 1.33 mmol, 1 eq., MW 430.29) inTHF (15 mL) at 23° C. was added Pd(PPh₃)₄ (153.6 mg, 0.133 mmol, 0.1eq., MW 1155.58) followed by dropwise addition of benzylzinc bromidesolution (3.2 mL, 1.6 mmol, 1.2 eq., 0.5 M). After 17.5 hours, water (10mL) was added to quench the reaction. The mixture was extracted withEtOAc (2×50 mL), dried with MgSO₄, and filtered. The organic layer wasconcentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product were combined and concentratedproviding a colorless oil that was used without further purification.

(R,E)-Ethyl 3-(4-hydroxyphenyl)-6-phenylhex-4-enoate (83.6). To astirred solution of 83.5 (405.8 mg, 1.03 mmol, MW 394.50) in EtOH (11mL) at 23° C. was added PPTS (catalytic). Stirring was continued for 16hours. The reaction was concentrated in vacuo. The residue was thenpurified by flash chromatography (SiO₂ gel 60, eluted with 0 to 20%EtOAc in hexanes). Fractions containing the desired product werecombined and concentrated providing a colorless oil. The desired productwas contaminated (˜5%) with a further olefinic product (believed tocontain a terminal double bond) and was used without furtherpurification.

(R,E)-6-Phenyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoicacid (83). Compound 83 was prepared by a method analogous to that ofGeneral Procedure A for 5.15.1. MS ESI (neg.) m/e: 481.3 (M−H). ¹H NMR(400 MHz) (CDCl₃) δ 7.25 (2H, s), 7.19 (2H, t, J=7.4 Hz), 7.14 (6H, m),6.87 (2H, d, J=8.6 Hz), 5.64 (2H, m), 4.88 (2H, s), 3.80 (1H, m), 3.27(2H, d, J=5.5 Hz), 2.67 (2H, m), 1.62 (4H, s), 1.21 (12H, s).

Example 84

Ethyl (3S)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-pentynoate(84.2). Compound 84.1 was prepared by a method based on that reported inBiochemistry 1989, 28, 3833-3842. To stirred solution of phenol 84.1(1.0 g, 4.6 mmol, 1 eq., MW 218.25) in DCM at 23° C. was added3,4-dihydro-2H-pyran (839 μL, 9.2 mmol, 2 eq., MW 84.12) followed byPPTS (catalytic, MW 251.31). The resulting mixture was stirred for 16hours and concentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product were combined and concentratedto a colorless oil (1.3 g, 94%). MS ESI (pos.) m/e: 325.1 (M+Na)⁺, 320.2(M+H₂O)⁺.

Ethyl(3S)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-5-(tributylstannanyl)-4-pentenoate(84.3). To a stirred solution of 84.2 (80.0 mg, 0.26 mmol, MW 302.37) inTHF at 23° C. was added PdCl₂(PPh₃)₂ (18.6 mg, 0.026 mmol, MW 701.89)followed by Bu₃SnH (84.0 μL, 0.32 mmol, MW 291.05). After the addition,the solution turned black. After a further 2 minutes, the mixture wasconcentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product 84.3 were combined andconcentrated providing a colorless oil (96.0 mg). ¹H NMR spectroscopyshowed the product to be a 3:1 ratio of 84.3:84.3a respectively.

Ethyl(3S,4E)-5-iodo-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-4-pentenoate(84.4). To a stirred solution of 84.3/84.3a (96.0 mg, 0.16 mmol, 1 eq.,MW 593.42) in THF (5 mL) at −78° C. was added iodine (45.0 mg, 0.18mmol, 1.1 eq., MW 253.81) in THF (2 mL) dropwise. After the addition wascomplete, a saturated solution of NaS₂O₃ and NaHCO₃ were added at thesame time to quench the reaction. EtOAc was added to the mixture, andthe resulting mixture was washed with NaHCO₃ (aq) (2×50 mL) and brine(1×50 mL). The organic layer was dried over MgSO₄ and filtered. Theorganic layer was concentrated in vacuo. The residue was then purifiedby flash chromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc inhexanes). Fractions containing the desired product were combined andconcentrated providing the product as a colorless oil (66 mg, 58% over 2steps). MS ESI (pos.) m/e: 453.0 (M+Na)⁺, 448.1 (M+H₂O)⁺.

(3S,E)-Ethyl6-phenyl-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)hex-4-enoate (84.5).To a stirred solution of 84.4 (321.9 mg, 0.748 mmol, 1 eq., MW 430.29)in THF (19 mL) at 23° C. was added Pd(PPh₃)₄ (86.8 mg, 0.075 mmol, 0.1eq., MW 1155.58) followed by dropwise addition of benzyl zinc bromidesolution (1.8 mL, 0.90 mmol, 1.2 eq., 0.5 M) After 3 hours, water (10mL) was added to quench the reaction. The mixture was extracted withEtOAc (2×50 mL), dried with MgSO₄, and filtered. The organic layer wasconcentrated in vacuo. The residue was then purified by flashchromatography (SiO₂ gel 60, eluted with 0 to 20% EtOAc in hexanes).Fractions containing the desired product were combined and concentratedproviding the product as a colorless oil that was used without furtherpurification.

(S,E)-Ethyl 3-(4-hydroxyphenyl)-6-phenylhex-4-enoate (84.6). To astirred solution of 84.4 (156.9 mg, 0.398 mmol, MW 394.50) in EtOH (5mL) at 23° C. was added PPTS (catalytic). Stirring was continued for 16hours. The reaction was concentrated in vacuo. The residue was thenpurified by flash chromatography (SiO₂ gel 60, eluted with 0 to 20%EtOAc in hexanes). Fractions containing the desired product werecombined and concentrated providing a colorless oil. The desired productwas contaminated (˜5%) with a further olefinic product (believed tocontain a terminal double bond) and was used without furtherpurification.

(S,E)-6-Phenyl-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)hex-4-enoicacid (84) Compound 84 was prepared by a method analogous to that ofGeneral Procedure A for 5.15.1. (MS ESI (neg.) m/e: 481.3 (M−H). ¹H NMR(400 MHz) (CDCl₃) δ 7.25 (2H, s), 7.19 (2H, t, J=6.7 Hz), 7.15 (6H, m),6.87 (2H, d, J=8.6 Hz), 5.64 (2H, m), 4.88 (2H, s), 3.80 (1H, m), 3.28(2H, d, J=5.5 Hz), 2.67 (2H, m), 1.62 (4H, s), 1.21 (12H, s).

6.89 Example 85

Compound 85.1 (commercially available from Maybridge) was reduced to85.2 using a procedure very similar to that described in JOC, 43,(1978), 2167. 85.2 was converted to 85.3 by simply treating it withthionyl chloride at room temperature.

(S)-3-(4-((2,2-Dimethyl-3,4-dihydro-2H-chromen-7-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (85). Compound 85 was obtained from compound M12 and 85.3 byfollowing General Procedure A. MS ESI (neg.) M/E: 419 (M−H).

6.90 Example 86

86.1 (commercially available from Maybridge) was converted to 86.2 bytreating it with thionyl chloride at room temperature.

(S)-3-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (86). Compound 86 was obtained from compound M12 and 86.2 byfollowing the general procedure A. MS ESI (neg.) M/E: 393 (M−H). ¹HNMR(DMSO-d₆) δ 7.6 (s, 1H), 7.5 (s, 1H), 7.2 (d, 2H), 6.9 (d, 2H),6.85-6.75 (overlapping signals, 3H), 4.9 (s, 2H), 4.8 (m, 1H), 4.2 (s,4H), 3.7 (s, 3H), 3.3 (dd, 1H), 3.0 (dd, 1H).

Cell-based Aequorin Assay

Cell-based aequorin assays were employed to characterize the modulatoryactivity of compounds on the GPR40 signaling pathway. In an exemplaryassay, CHO cells were stably transfected with both GPR40 and Aequorin(Euroscreen). Cells were detached from the tissue culture dish with 2 mLof trypsin (0.25% (w/v)). Trypsinization was halted with 28 mL of HanksBuffered Salt Solution containing 20 mM Hepes (H/HBSS) and 0.01% fattyacid-free human serum albumin (HSA). Coelantrazine is added to 1 ug/mL,and the cells were incubated for 2 hours at room temperature. Compoundswere dissolved in DMSO for preparation of 10 mM stock solutions.Compounds were diluted in H/HBSS containing 0.01% HSA. Serial dilutionsof the test compounds were prepared to determine dose response.

Aequorin luminescence measurements were made using an EG&G Berthold96-well luminometer, and the response was measured over a 20 secondinterval after cells and compounds were mixed. The maximum relativelight units was plotted to determine dose response. The EC₅₀ (effectiveconcentration to reach 50% maximal response) was determined from thedose response plot.

Table 1 presents representative data (EC₅₀ values) obtained forexemplary compounds of the invention for the relative activation ofhuman GPR40.

The stereoisomers in Table 1 are as specified, i.e., S-enantiomers orR-enantiomers, and if not specified, or if shown with wavy bonds, aremixtures of S-enantiomers and R-enantiomers. In addition, the presentinvention provides the S-enantiomers, the R-enantiomers, and mixtures ofboth S-enantiomers and R-enantiomers including racemates of eachcompound prepared according to the synthetic methods described herein oradapted with the necessary minor modifications from these methods.

Insulin Secretion Assay

Human islets were isolated from cadaveric donors. Islets were treatedwith trypsin (0.25% (w/v) and cells were seeded in 96-well platescontaining 3,000 cells per well. Cells were cultured in Roswell ParkMemorial Institute (RMPI) media containing 10% fetal bovine serum.

For determination of insulin secretion, media was removed from isletcells and replaced with Krebs-Ringer bicarbonate buffer containing 10 mMHEPES (KRBH) and 2 mM glucose. After one hour incubation, media wasreplaced with KRBH containing 11.2 mM glucose and test compounds.Insulin released into the medium from the islet cells was measured usingscintillation proximity assay (SPA). The compounds of Examples 4 and 9stimulated insulin secretion from islet cells with EC₅₀ values of lessthan 1 uM.

For determination of insulin secretion from rodent islets, C57/B16 miceare euthanized with carbon dioxide gas. The pancreatic bile duct isclamped proximal to the duodenum and then cannulated. H/HBSS containing0.75 mg/mL collagenase XI (Sigma) is then infused into the pancreasthrough the cannula. The pancreas is excised and then incubated at 37°C. for 13 minutes to complete enzymatic digestion. The collagenasedigestion is quenched in H/HBSS containing 1% BSA and washed once in thesame buffer. Islets can be purified using density gradientcentrifugation using Histopaque (Sigma) and are hand-picked under astereomicroscope.

Islets are cultured overnight in Roswell Park Memorial Institute (RMPI)media containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol.Following overnight culture, islets are incubated in KRBH containing 2.8mM glucose for one hour.

For determination of insulin secretion, islets are incubated in DMEMcontaining 12.5 mM glucose and test compounds for one hour. Insulinreleased into the culture medium from the islets is measured using aninsulin ELISA.

TABLE 1 Aequorin Assay Using Human GPR40 No. Structure^(a) Relative EC₅₀^(b) 1

+++ 2

+++ 3

++++ 4

+++ 5

+++ 6

++++ 7

++ 8

++ 9

++ 10

+++ 11

++++ 12

+++ 13

+ 14

+++ 15

+++ 16

+++ 17

+ 18

+++ 19

++ 20

++ 21

A^(d) 22

A^(d) 23

A^(d) 24

A^(d) 25

A^(d) 26

A^(d) 27

A^(d) 28

A^(d) 29

A^(d) 30

A^(d) 31

++ 32

+++ 33

A^(d) 34

A^(d) 35

A^(d) 36

A^(d) 37

A^(d) 38

A^(d) 39

A^(d) 40

A^(d) 41

A^(d) 42

A^(d) 43

A^(d) 44

A^(d) 45

A^(d) 46

A^(d) 47

A^(d) 48

A^(d) 49

A^(d) 50

A^(d) 51

A^(d) 52

A^(d) 53

A^(d) 54

A^(d) 56

A^(d) 57

A^(d) 58

A^(d) 59

A^(d) 60

A^(d) 61

A^(d) 62

+++ 63

+ 64

+++ 65

+++ 66

A^(d) 67

A^(d) 68

A^(d) 69

A^(d) 70

A^(d) 71

A^(d) 72

++++ 73

+++/++++ 74

++++ 75

+++ 76

++++ 77

++++ 78

+++ 79

++ 80

+++ 81

++ 82

+++ 83

++ 84

++ 85

++ 86

++ ^(a)When present, the “

” bond indicates a mixture of stereoisomers are present in the exemplarycompound. ^(b)EC₅₀ Ranges: + EC₅₀ > 10 μM ++ 1 μM ≦ EC₅₀ ≦ 10 μM +++ 0.1μM ≦ EC₅₀ < 1 μM ++++ 0.01 μM ≦ EC₅₀ < 0.1 μM +++++ EC₅₀ < 0.01 μM^(c)Aequorin assay data from transiently transfected cell line. ^(d)Thiscompound is tested using the methods described herein and is found tohave an EC₅₀ of less than or about 10 μM.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Each publication and patent application citedherein is incorporated in its entirety as if fully set forth herein.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1. A compound having the formula I:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a tautomer or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a mixture thereof, wherein Q ishydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; L¹ is abond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b));

represents an optionally substituted benzo-fused (C₅-C₈)cycloalkane ringcomprising a benzene ring fused to a (C₅-C₈)cycloalkane ring, anoptionally substituted heterobenzo-fused (C₅-C₈)cycloalkane ringcomprising a six-membered heteroaryl ring comprising 1 or 2 N atomsfused to a (C₅-C₈)cycloalkane ring, or a heteroaryl-fused(C₅-C₈)cycloalkane ring comprising a five-membered heteroaryl ringcomprising 1 or 2 heteroatoms fused to a (C₅-C₈)cycloalkane ring,wherein the benzene ring of the benzo-fused (C₅-C₈)cycloalkane ring, theheteroaryl ring of the heterobenzo-fused (C₅-C₈)cycloalkane ring, or theheteroaryl ring of the heteroaryl-fused (C₅-C₈)cycloalkane ring isbonded to L² or M, if L² is a bond; L² is a bond, (C₁-C₆)alkylene,(C₂-C₆)heteroalkylene, oxymethylene, O, S(O)_(k), N(R^(a)),C(O)N(R^(b)), SO₂N(R^(b)), (C₁-C₄)alkylene-C(O)N(R^(b)),(C₁-C₄)alkylene-N(R^(b))C(O), (C₂-C₄)alkenylene-C(O)N(R^(b)),(C₂-C₄)alkenylene-N(R^(b))C(O), (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, (C₂-C₄)alkenylene-SO₂N(R^(b)), or(C₂-C₄)alkenylene-N(R^(b))SO₂; M is an aromatic ring, a heteroaromaticring, (C₅-C₈)cycloalkylene, aryl(C₁-C₄)alkylene, orheteroaryl(C₁-C₄)alkylene; X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k); L³is a (C₁-C₅)alkylene or (C₂-C₅)heteroalkylene; A is —CO₂H,tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃,thiazolidinedionyl, hydroxyphenyl, or pyridyl; R^(a) is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or (C₂-C₆)heteroalkyl; R^(b) ishydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; R¹ is cyano, aryl,heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³; R^(1′) is hydrogen,cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl; R² and R³ areindependently selected from hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl;optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached comprisingfrom 0 to 2 additional heteroatoms selected from N, O, or S; and thesubscript k is, in each instance, independently selected from 0, 1, or2, wherein, R¹ is a group other than a group of the following formula:


2. The compound of claim 1, wherein

is a benzo-fused (C₅-C₈)cycloalkane ring.
 3. The compound of claim 1,wherein

is a heterobenzo-fused (C₅-C₈)cycloalkane ring, wherein the heteroarylring of the heterobenzo-fused (C₅-C₈)cycloalkane ring comprises 1 or 2 Natoms.
 4. The compound of claim 1, wherein the (C₅-C₈)cycloalkane ringcomprises 0-3 heteroatoms selected from N, O, and S.
 5. The compound ofclaim 1, wherein the compound has the formula II:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a tautomer or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a mixture thereof, wherein Q isselected from hydrogen, aryl, or heteroaryl; L² is selected from(C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O, or S(O)_(k); R¹is selected from (C₂-C₈)alkynyl, aryl, heteroaryl, heterocycloalkyl, or—C(O)NR²R³; R² and R³ are independently selected from hydrogen or(C₁-C₄)alkyl; R⁴ is independently selected from substituted(C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, —(C₂-C₈) alkynyl, —(C₂-C₅)alkenyl, or —NO₂, where R′, R″and R′″ each independently refer to hydrogen, unsubstituted (C₁-C₈)alkylor heteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ is independentlyselected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; thesubscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,or 14; andthe subscript p is 0, 1, 2, 3 or
 4. 6. The compound of claim 5, whereinR⁴ independently is selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,cyano, or nitro.
 7. The compound of claim 5, wherein the compound hasthe formula IIIA or IIIB:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.
 8. The compound of claim 1, wherein thecompound has the formula IV:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a tautomer or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a mixture thereof, wherein R^(4′)is independently selected from substituted (C₁-C₆)alkyl, —R′, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; one of R⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the othersof R⁶ and R^(6′) are independently selected from H, (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro, wherein one of R⁶ and one ofR^(6′) on adjacent or non-adjacent carbon atoms, or on the same carbonatom may join together to form a C₅-C₈ cycloalkane ring, or two of R⁶ ortwo of R^(6′), on adjacent or non-adjacent carbon atoms, may jointogether to form a C₅-C₈ cycloalkane ring; the subscript n′ is 0, 1, 2,or 3; and the subscript m is 1, 2, 3, or
 4. 9. The compound of claim 8,wherein the compound has the formula V:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a tautomer or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a mixture thereof.
 10. The compoundof claim 8, wherein the compound has the formula VI:

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof; or a tautomer or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a mixture thereof.
 11. The compoundof claim 8, wherein the subscript m is 1 or
 2. 12. The compound of claim8, wherein the subscript m is 1 or 2; the subscript n′ is 0; L¹ is abond; L² is selected from —CH₂—O—, substituted oxymethylene, or O; R¹ isselected from aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)alkynyl; R^(1′) is H; and A is—CO₂H.
 13. The compound of claim 8, wherein Q is H; L³ is CH₂; and L² is—CH₂—O— or —CH(CH₃)—O—.
 14. The compound of claim 8, wherein R⁶ andR^(6′) are independently selected from H and methyl and at least two ofR⁶ and R^(6′) are methyl groups.
 15. The compound of claim 8, wherein R⁶and R^(6′) are independently selected from H and methyl and at leastfour of R⁶ and R^(6′) are methyl groups.
 16. The compound of claim 1,wherein R¹ is selected from heteroaryl or heterocycloalkyl.
 17. Thecompound of claim 16, wherein R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl.
 18. The compound of claim 1, wherein the compound has theformula of any one of XIa-XIm:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof, wherein R^(4′) is independently selectedfrom substituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″ SO₂R, —CN, —(C₂-C₅)alkynyl, —(C₂-C₅)alkenyl, or —NO₂, where R′, R″and R′″ each independently refer to hydrogen, unsubstituted (C₁-C₈)alkylor heteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; the subscript n′ is 0, 1,2, or 3; and R^(d) is selected from optionally substituted C₁-C₆ alkylor optionally substituted aryl.
 19. The compound of claim 1, wherein

is a heteroaryl-fused (C₅-C₈)cycloalkane ring and the heteroaryl of theheteroaryl-fused (C₅-C₈)cycloalkane ring is selected from thiophene,furan, pyrrole, oxazole, thiazole, or imidazole.
 20. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier, diluent,or excipient, and the compound of claim
 1. 21. A method for treating adisease or condition, comprising: administering to a subject in needthereof, a therapeutically effective amount of the compound of claim 1,wherein the disease or condition is a disease or condition responsive tothe modulation of GPR40.
 22. A method of synthesizing a compound offormula XV, the compound of formula XV having the following structure:

the method comprising: (a) reacting a compound of formula XIII with acompound of formula XIV to produce the compound of formula XV, whereinthe compounds of formula XIII and XIV have the following structures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)alkynyl, or —C(O)NR²R³; R² and R³ are independently selected fromhydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl,(C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl; optionally, R² and R³ arecombined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogenatom to which they are attached comprising from 0 to 2 additionalheteroatoms selected from N, O, or S; and; R⁵ is independently selectedfrom (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; p isselected from 0, 1, 2, 3, or 4; z is selected from 1, 2, or 3; R^(4′) isindependently selected from substituted (C₁-C₆)alkyl, —R′, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, —(C₂-C₅)alkynyl,—(C₂-C₅)alkenyl, or —NO₂, wherein R′, R″ and R′″ are each independentlyselected from hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; n′ is 0, 1, 2, or 3; m is 1,2,3, or 4; one ofR⁶ and R^(6′) is L¹ or Q, if L¹ is a bond, and the others of R⁶ andR^(6′) are independently selected from H, (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or nitro, wherein one of R⁶ and one of R^(6′) onadjacent or non-adjacent carbon atoms, or on the same carbon atom mayjoin together to form a C₅-C₈ cycloalkane ring, or two of R⁶ or two ofR^(6′), on adjacent or non-adjacent carbon atoms, may join together toform a C₅-C₈ cycloalkane ring; L¹ is selected from a bond,(C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)); R^(a) is selected fromhydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or (C₂-C₆)heteroalkyl; R^(b)is selected from hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; Q isselected from hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; W is a leaving group; and further wherein, thecompounds of formula XIII and XV can be a mixture of compounds havingthe R and S stereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.
 23. The method of claim 22,wherein W is selected from OH, a halogen, an OTs, an OMs, or an OTfwherein Ts is p-toluenesulfonyl, Ms is methanesulfonyl, and Tf istrifluoromethanesulfonyl.
 24. The method of claim 22, wherein Alk ismethyl or ethyl.
 25. The method of claim 22, wherein m is 1 or 2.